XLID

Information posted on this page is intended to complement and update the Atlas on X-Linked Mental Retardation (now termed Intellectual Disability) by R.E. Stevenson, C.E. Schwartz, and R.J. Schroer (X-Linked Mental Retardation, Oxford University Press, 2000).

New X-linked intellectual disability syndromes, new gene localizations, revised gene localizations, and gene identifications are presented in abbreviated form with appropriate references. Four graphics show gene localizations, linkage limits, and recurrent microduplications and microdeletions. A table gives gene identifications in chronological order.

1. New Syndromes and Localizations | MRX Families, Loci and Genes
2. Genes Cloned
3. Segmental X Chromosome Duplications
4. Maps (4) and Table of Gene Identifications

New Syndromes and Localizations

• Abidi syndrome (Abidi et al., Am J Med Genet 85:223, 1999). Based on 8 affected males in 3 generations with variable IQ level, stature, head circumference, sloping of forehead, hearing loss, cupped ears and testicular volume; carriers have no manifestations; linkage between AR (Xq12) and DXS366 (Xq21) (maximum lod score 4.41 at DXS1166).
• Chaissaing chondrodysplasias (Chaissaing et al. Am J Med Genet 136A:307, 2005). This spondylometaphyseal dysplasia has hydrocephaly, microphthalmia and early lethality in males; spondylometaphyseal changes, rhizomelic limb shortening and learning disability in females. The gene, HDAC6, is located in Xp11.23.
• CK syndrome (du Souich et al., Am J Med Genet 149A:2469, 2009). Based on seven males in one family with variable ID, microcephaly, cortical changes, long thin face with upslanted palpebral fissures and micrognathia, asthenic build, hypotonia, hyperextensible joints and seizures. A 3bp deletion was found in the NSDHL gene which has been implicated in CHILD syndrome.
• Craniofacioskeletal syndrome. Stevenson et al. (Am J Med Genet 143:2321, 2007). Based on one family with seven females with mild ID, microcephaly, short stature, small ears, full nasal tip, short philtrum, small mandible, small hands and feet, and excessive fingerprint arches. The females had marked skewing of X-inactivation and linkage studies suggest the gene locus to be in Xq26-q27. Males died in infancy with IUGR, broad cranium with wide sutures and fontanelles, cardiac defects and genital abnormalities.
• Giuffré–Tsukahara syndrome. A syndrome with XLID, microcephaly, and radioulnar synostosis has been reported (Gaspar et al. AJMG 146A:1453, 2008; Guiffré et al. AJMG 51:266, 1994; Tsukahara et al. AJMG 58:159, 1995; Udler et al. AJMG 80:526, 1998; Selicorni et al. AJMG 132A:189, 2005). There appears to be variable facial findings and intellectual disability. Linkage has not been achieved and causal heterogeneity cannot be excluded.
• Hall Orofacial syndrome (Hall et al., Am J Hum Genet 65:A151, 1999). This apparently X-linked syndrome in three males has cleft lip + cleft palate, hypertelorism and inguinal hernias. The gene locus was not mapped.
• Homfray Seizures-contractures (Homfray et al., Clin Dysmorphol 4:289, 1995). A boy and his uncle had coarse facies, seizures and progressive joint contractures.

• Martin et al. (J. Med Genet 37:836, 2000) described three males in one family with microcephaly, short stature, telecanthus, umbilical hernia, hearing loss and other inconsistent features. They later described a missense mutation in RAB40AL which encodes a Ras-like GTPase (Int Congress Hum Genet, Montreal, October 2011).

• MRXS7 (Ahmad et al., Eur J Hum Gen 7:828, 1999). Based on a Pakistani family with 10 affected males showing mild to moderate ID, obesity, tapering fingers, flat feet, hypogonadism (small testes, micropenis, absence of body hair), malformation and malposition of teeth, and diminished strength; carriers have no intellectual deficit; linkage to pericentromeric region between DXS8083 (Xp11.3) and DXS8112 (Xq23) (maximum lod score 3.86 at DXS1106).
• Roifman syndrome. This syndrome has been reported in seven males and is characterized by spondyloepiphyseal dysplasia, prenatal and postnatal growth deficiency, retinal dystrophy, B-cell immunodeficiency and variable cognitive impairment (Roifman, Clin Genet 55:103, 1999; de Vries et al., J Int Disab Res 50:690, 2006). All reported individuals being males suggests X-linkage, but this has not been proven.
• Shrimpton syndrome, MRXS9 (Shrimpton et al., Am J Med Genet 84:293, 1999). Based on 9 affected males with severe ID, short stature, microcephaly, and strabismus; carriers may have learning difficulties; linked to Xq12-q21.31 between AR (Xq12) and DXS1217 (Xq21.3) (maximum lod score 4.34 at DXS1111 and DXS1197).
• Turner et al. (Am J Med Genet 117A:245, 2003) describe an XLID syndrome with severe ID, childhood hypotonia and aggressive adult behavior. There was a tendency to long narrow face with small head and pointed chin, large ears, and general asthenia. Linkage was found to Xp22 (lod score 4.8). The gene for both this condition, MRX59, and Fried syndrome has now been identified as AP1S2 (Tarpey et al. Am J Hum Genet 79:1119, 2006; Saillour et al., J Med Genet 44:739, 2007).
• Vitale et al. (Am J Med Genet 103:1, 2001) described a family in which 8 males had no speech, coarse facies, downslanting palpebral fissures, large bulbous nose, macrostomia, hypoplastic earlobe and short stature. The entity was mapped to a 16cM region in Xq24 (maximum lod score 3.61 at DSX1001).
• X-linked cerebral-cerebellar-coloboma syndrome. Two brothers with hydrocephalus, cerebellar vermis hypoplasia, agenesis of the corpus callosum, retinal colobomas, hypertelorism, small nose, micrognathia, severe developmental delay, hypotonia, seizures, absent reflexes, irregular respiratory pattern and death before age 4 years were reported by Kroes et al. (Am J Med Genet 135A:297, 2005). A similarly affected half sibling conceived by donor insemination died following delivery. The authors considered this to likely represent a new XLID syndrome that resembled Joubert syndrome. A daughter also had severe intellectual disability, but was not described further.
• X-linked Cornelia de Lange syndrome - See Section II for gene (SMC1L1/SMC3L1) in Xp11.2.
• X-linked hypoparathyroidism. Usually leads to infantile hypocalcemia, hypophosphatemia, seizures and death in males; survivors may have cataracts, short stature and intellectual disability. Females show no clinical or metabolic phenotype. The entity is linked to Xq27, but the gene has not been isolated (Peden, Am J Hum Genet 12:323, 1960; Whyte and Weldon: J Pediatr 99:608, 1981; Thakker et al.: J Clin Invest 86:40, 1990).
• XLID-aphasia-seizures-prognathism was reported initially as MRX82 and localized to Xq24-q25 (Martinez et al., Am J Med Genet 131A:174, 2004; Tejada et al., 13th Workshop on Fragile X and XLMR:P78, 2007).
• XLID-choreoathetosis, MRXS10 (Reyniers et al., Am J Hum Genet 65:1406, 1999). Based on 5 affected males with mild ID, arachnodactyly, infancy-onset choreoathetosis, and aggression/agitation or psychosis; no carrier manifestations; linkage to Xp11 between DXS1201 (Xp11.4) and DXS991 (Xp11.2) (maximum lod score 2.14 at DXS8080 and DXS8054). Lenski et al. (Am J Hum Genet 80:372, 2007) identified a missense mutation in HADH2 in this family (see Section II).
• XLID-coarse facies (Shashi et al., Am J Hum Genet 66:469, 2000). Based on 9 affected males in 4 generations showing coarse facies, puffy eyelids, narrow palpebral fissures, prominent supraorbital ridges, large ears, bulbous nose, prominent lower lip, obesity, and macroorchidism; carriers have normal intellect but may have cephalometric changes; linkage between Xq26q27 between ATA59C05 (Xq26) and GATA31E08 (Xq27) (maximum lod score 3.1 at DXS1047). A second family with similar clinical features was reported by Castro et al. (Am J Med Genet 118A:49, 2003). Haplotype analysis was consistent with localization of Shashi XLID-coarse facies in Xq26-q27.
• XLID-hydrocephaly-microphthalmia-chondrodysplasia. A lethal chondrodysplasia was described in four males (3 fetuses and 1 infant) by Chassaing et al., Am J Med Genet 136A:307, 2005). Radiographic findings included poor mineralization of skull, marked platyspondyly, long clavicles, hypoplastic iliac wings, poor ossification of pubis, brachydactyly with metaphyseal cupping of the metacarpals, metatarsals and phalanges, and malformed calcaneus. Hydrocephaly, microphthalmia, low-set ears, and short nose were present. Affected females had short stature and mild intellectual disability. The responsible gene, HDAC6, is located in Xp11.23.
• XLID-hypogonadism-tremor (Cabezas et al., J Med Genet 37:663, 2000). Based on 6 affected males in 3 generations showing severe ID, short stature, obesity, prominent lower lip, high palate, small feet, hyperextensible joints, kyphosis, small testes, muscle wasting of legs, wide based gait or absent ambulation, poor fine motor coordination, impaired or absent speech, fine tremor, and behavioral aberrations; only carrier examined showed learning difficulty and fine tremor; linkage between DXS424 (Xq24) and DXS1047 (Xq25) (maximum lod score 2.80 at DXS1212). This family was found to have a mutation in CUL4B (Tarpey et al., Am J Hum Genet 80:345, 2007 - see Section II).
• XLID-microcephaly-testicular failure. Cilliers et al. (Eur J Med Genet 50:216, 2007) reported a family in which four males had ID, microcephaly, hypogonadism, and short stature. Linkage studies were not conclusive but suggested localization in Xq25-q27.
• XLID-nail dystrophy-seizures. Nascimento et al. (Am J Hum Genet 79:549, 2006) reported a missense mutation in a ubiquitin deficiency enzyme, UBE2A, in three males with facial dysmorphism, short wide neck, low posterior hairline, widely spaced nipples, small penis, nail dystrophy, hirsutism, dry skin, seizures and severe speech impairment. Obligate carriers appeared normal and had marked skewing of X inactivation. The gene is located in Xq24-q25. Testing of other linked families was negative.
• XLID-precocious puberty, was reported in three males in two generations by Hockey (Am J Med Genet 23:127, 1986). Carrier mothers had normal intelligence, but were obese; one was found to have a deletion of 15q11-q13.
• XLID-spondyloepimetaphyseal dysplasia (Bieganski et al., Eur J Pediatr 158:809, 1999). Based on 3 male cousins with mild ID or slow development, short stature, low frontal hairline, hypertelorism, broad nasal tip, pale optic discs, prominent eyebrows, lowset ears, high palate, short neck, and a generalized bony dysplasia affecting the spine, epiphyses, and metaphyses; carriers have no manifestations; no linkage information.
• XIDE. An X-linked intellectual disability syndrome with infantile onset epilepsy (not infantile spasms) has been mapped to Xp21.1-p11.4 maximum lod score 3.83 for several markers (Hedera et al., Ann Neurol 51:45, 2002). The gene responsible (ATP6AP2) has been reported by Ramser et al. (Hum Mol Genet 14:1019, 2005). This condition appears to be separate from West syndrome (due to ARX mutations), another X-linked seizure disorder caused by mutations in CDKL5, and the Epilepsy-ID syndrome localized to Xq22 with expression in females caused by mutations in PCDH19 (Dibbens et al., Nat Genet 40:776, 2008).

MRX Families, Loci and Genes

• MRX1: IQSEC2, Xp11.2 (Shoubridge et al. Nat Genet 42:486, 2010)
• MRX2: Xp22.3
• MRX3: Xq28-qter
• MRX4: Xp11.22-Xq21.31
• MRX5: Xp21.1-Xq21.3
• MRX6: Xq27
• MRX7: Xp11.23-Xq12
• MRX8: DLG3 (unpublished, Schwartz et al.)
• MRX9: FTSJ1 - Xp11.23 (Ramser et al. J Med Genet 41:679, 2004)
• MRX10: Xp11.4-Xp21.3
• MRX11: Xp11.22-Xp21.3
• MRX12: Xp21.2-Xq12
• MRX13: Xp22.3-Xq22
• MRX14: Xp11.22-Xq12
• MRX15: Xp22.1-Xq12
• MRX16: MECP2 - Xq28 (Couvert et al. Hum Mol Genet 15:941, 2002)
• MRX17: Duplication of Xp11.22 - RIBC1, HSD17B10, and HUWE1 (Froyen et al. Am J Hum Genet 82:432, 2008)
• MRX18: IQSEC2, Xp11.2 (Shoubridge et al. Nat Genet 42:486, 2010)
• MRX19: RPSKA3 (RSK2) - Xp22.2-Xp22.1 (Merienne et al. Nat Genet 22:13, 1999)
• MRX20: Xp21.1-Xq23
• MRX21: IL1RAPL1, Xp22.1 (Tabolacci et al., Am J Med Genet 140A:482, 2006)
• MRX22: Xp11-cent
• MRX23: Xq23-Xq24
• MRX24: Xp22.2-Xp22.3
• MRX25: Xq27.3
• MRX26: Xp11.4-Xq23
• MRX27: Xq24-Xq27.1
• MRX28: Xq27.3-qter
• MRX29: ARX - Xp22.13 (Stepp et al. MBC Med Genet 6:16, 2005)
• MRX30: PAK3 - Xq21.3-Xq24 (Allen et al. Nat Genet 20:25, 1998)
• MRX31: Duplication of Xp11.22 - RIBC1, HSD17B10, and HUWE1 (Froyen et al. Am J Hum Genet 82:432, 2008)
• MRX32: ARX - Xp22.13 (Stepp et al. MBC Med Genet 6:16, 2005)
• MRX33: ARX - Xp22.13 (Stepp et al. MBC Med Genet 6:16, 2005)
• MRX34: IL1RAPL1, Xp22.1 (Raeymaekers et al., Am J Med Genet 64:16, 1996)
• MRX35: Xq21.3-Xq26
• MRX36: ARX, Xp22.13 (Frints et al., Am J Med Genet 112:427, 2002)
• MRX37: Xp22.31-Xp22.32
• MRX38: ARX - Xp22.13 (Stepp et al. MBC Med Genet 6:16, 2005)
• MRX39: Xp11
• MRX40: Xq28
• MRX41: GDI1 - Xq28 (Bienvenu et al. Hum Mol Genet 7:1311, 1998)
• MRX42: Xq24-Xq25
• MRX43: ARX, Xp22.13 (Bienvenu et al., Hum Mol Genet 11:981, 2002)
• MRX44: FTSJ1 - Xp11.23 (Freude et al. Am J Hum Genet 75:305, 2004)
• MRX45: ZNF81 - Xp22.1-Xp11 (Kleefstra et al. J Med Genet 41:394, 2004)
• MRX46: ARHGEF6 - Xq26 (Kutsche et al. Nat Genet 26:247, 2000)
• MRX47: PAK3 - Xq21.3-Xq24 (Bienvenu et al. Am J Med Genet 93:294, 2000)
• MRX48: GDI1 - Xq28 (D'Adamo et al. Nat Genet 19:134, 1998, Bienvenu et al. Hum Mol Genet 7:1311, 1998)
• MRX49: Xp22.1-pter
• MRX50: Xp11.4-p11.21
• MRX51: Xp11.4-p11.3
• MRX52: Xp11.21-q21.32
• MRX53: Xq22.2-q26
• MRX54: ARX, Xp22.13 (Bienvenu et al., Hum Mol Genet 11:981, 2002)
• MRX55: PQBP1, Xp11.2 (Kalscheuer et al., Nat Genet 35:313, 2003)
• MRX56: Xp21.1-p11.21
• MRX57: Xq24-q25
• MRX58: TM4SF2, Xp11.4 (Zemni et al., Nat Genet 24:167, 2000)
• MRX59: AP1S2, Xp22 (Tarpey et al., Am J Hum Genet 79:1119, 2006)
• MRX60: OPHN-1, Xq12 (Billuart et al., Nature 392:923, 1998)
• MRX61: Xq13.1-q25
• MRX62: UPF3B (Laumonnier et al., Mol Psychiatry 2009 Feb 24 Epub ahead of print)
• MRX63: FACL4, Xq22 (Meloni et al., Nat Genet 30:436, 2002)
• MRX64: Xq28, MECP2 dup , same as Pai syndrome (Pai et al., J Med Genet 34:529, 1997; Friez et al., Pediatrics 118:e1687, 2006).
• MRX65: Xp11.3-Xq21.33 (Yntema et al., Am J Med Genet 85:205, 1999)
• MRX66: Xq21.33-q23
• MRX67: Xq13.1-q21.31
• MRX68: FACL4 (Longo et al., J Med Genet 40:11, 2003)
• MRX69: Xp11.21-q22.1
• MRX70: Xq23-q25
• MRX71: Xq24-q27.1
• MRX72: Xq28 (Russo et al., Am J Med Genet 94:376, 2000); mutation in RAB39B (Giannandrea et al. Am J Hum Genet 86:185, 2010).
• MRX73: Xp22-p21 (Martinez et al., Am J Med Genet 102:200, 2001)
• MRX74: Xp11.3-p11.4
• MRX75: Xq24-q26 (Caspari et al., Am J Med Genet 93:290, 2000)
• MRX76: ARX, Xp22.13 (Bienvenu et al., Hum Mol Genet 11:981, 2002)
• MRX77: Xq12-q21.33 (Sismari et al., Am J Med Genet 122A:46, 2003)
• MRX78: Xp11.4-p11.23 (DeVries et al., Am J Med Genet 111:443, 2002)
• MRX79: MECP2, Xq28 (Winnepenninckx et al., Hum Mutat 20:249, 2002)
• MRX80: Xq22-q24 (Verot et al., Am J Med Genet 122A:37, 2003)
• MRX81: Xp11.2-Xq12 (Annunziata et al., Am J Med Genet 118A:217, 2003)
• MRX82: Xq24-q25 (Martinez et al., Am J Med Genet A 131:174, 2004)
• MRX83:
• MRX84: Xp11.3-q22.3 (Zhang et al., Am J Med Genet 129A:286, 2004)
• MRX85: Xp21.3-p21.1 (DeBrouwer et al., Hum Mutat 28:207, 2007)
• MRX86:
• MRX87: ARX, Xp22.13 (LaPeruta et al., BMC Med Genet 8:25, 2007)
• MRX88: AGTR2, Xq24 (Vervoort et al., Science 296:20401, 2002)
• MRX89: ZNF41, Xp11.3 (Shoichet et al., Am J Hum Genet 73:1341, 2003)
• MRX90: DLG3, Xq13 (Tarpey et al., Am J Hum Genet 75:318, 2004)
• MRX91: t(X:15)(q13.3; cent) in female patient; ZDHHC15 mutation? (Mansouri et al., Eur J Hum Genet 13:970, 2005)
• MRX92: ZNF674, Xp11.3 (Lugtenberg et al., Am J Hum Genet 78:215, 2006)
• MRX93:
• MRX94:
• MRX95: MAGT1/OSTb, Xq21.1 (Molinari et al., Am J Hum Genet 82:1150, 2008).

Other MRX Genes

• NLGN4 CDKL5 (STK9)
• ZNF41 KDM5C, SMX (JARID1C)
• FGDY
• SCL16A2 (MCT8) ATRX (XNP)
• AFF2 (FMR2) SLC6A8

Genes Cloned

• AGTR2: The angiotensin II receptor type 2 has been implicated in XLID with optic atrophy and nonsyndromal XLID (Vervoort et al., Science 296:2401, 2002). The gene is located in Xq24. Mutations in a number of individuals and several XLID families were described. Additional mutations were identified by another group (Ylisaukko-oja et al., Hum Genet 114:211, 2004). The possibility that mutations reported in AGTR2 may be rare and non-disease-associated polymorphisms has been raised by Bienvenu et al. (J Med Genet 40:357, 2003) and Huang et al. (Am J Med Genet 139A:243, 2005).
• alpha-PIX: An X:21 translocation in a male with ID was found to disrupt a Rho guanine nucleotide exchange factor (ARHGEF6 or alpha-PIX) (Kutsche et al., Nat Genet 26:247, 2000). The male has severe ID, sensorineural hearing loss and mild dysmorphic features. Another mutation, in the first intron (IV31-11T-C) was identified in MRX46. This mutation apparently results in a proportion of mRNA to be synthesized using exon 2 which contains a portion of the CH (calponin homology) domain. The authors (ibid) propose the presence of this altered mRNA gives rise to the MRX46 phenotype.
• AP1S2: Tarpey et al. (Am J Hum Genet 79:1119, 2006) reported mutations in the sigma 2 subunit of the Adaptor Protein 1 Complex (Xp22) in three families including Turner syndrome (Turner et al., Am J Med Genet 117A:245, 2003) and MRX59 (Carpenter et al., Am J Med Genet 85:266, 1999). The gene is the first XLID gene to be involved in assembly of endocytic vesicles. Saillour et al. (J Med Genet 44:739, 2007) reported an intronic mutation that resulted in exon skipping and a nonsense mutation in two families with XLID-hydrocephaly-basal ganglia calcifications (Fried syndrome). Borck et al. (Hum Mutat 29:966, 2008) reported elevated CSF protein in two families including the original family with Fried syndrome.
• ARHGEF9: A missense mutation (164G>C) was found in a child with hyperekplexia, seizures, and profound psychomotor deterioration (Harvey et al., J Neurosci 24:5816, 2004)
• ARX: Mutations in the human ortholog of Aristaless (Xp22.2) were found to cause XLID in association with epilepsy (Strømme et al. Nat Genet 30:441, 2002). Novel mutations were found in 9 families with either syndromal or non-syndromal XLID. The syndromal XLID conditions were Partington syndrome and West syndrome. The epilepsy observed in patients included infantile spasms, myoclonic seizures and dystonia. Mutations have also been found in MRX 29, 32, 33, 36, 43, 54 and 76 (Bienvenu et al., Hum Mol Genet 11:981, 2002; Frints et al., Am J Med Genet 112:427, 2002; Stepp et al., BMC Med Genet 6:16, 2005). Two mutations, present in 7 families, were expansions of polyalanine tracts. Proud syndrome, X-linked lissencephaly with abnormal genitalia, and hydranencephaly have also been attributed to ARX mutations (Kitamura et al., Nat Genet 32:359, 2002; Uyanik et al., Neurology 61:232, 2003; Kato et al., Hum Mutat 23:147, 2004). Thus, mutations in ARX may account for a relatively large fraction of males with ID plus epilepsy. Reexamination of several families initially reported as MRX with ARX mutations have shown that affected individuals may develop seizures, autism, and dystonic hand movements (Turner et al., Am J Med Genet 112:405, 2002; Frints et al., Am J Med Genet 112:427, 2002). Focal hand dystonia was the most common neurological finding in 5 families reported by Nawara et al. (Am J Med Genet 140A:727, 2006).
• ATP6AP2: Mutation in the renin receptor gene (ATP6AP2) has been found in the single family reported with an XLID-epilepsy syndrome (XIDE), which maps to Xp11.4 (Ramser et al. Hum Mol Genet 14:1019, 2005).
• ATRX (XNP): Mutations in the gene responsible for XLID-hypotonic facies (alpha-thalassemia intellectual disability) have now been described in the original families with Carpenter-Waziri syndrome (Abidi et al., Am J Med Genet 85:249, 1999), Holmes-Gang syndrome (Stevenson et al., Am J Med Genet 94:383, 2000), and Chudley-Lowry syndrome (Abidi et al., Eur J Hum Genet 13:176, 2005). Mutations have also been described in a family believed to have Juberg-Marsidi syndrome (Villard et al., Nat Genet 12:359, 1996) and a family believed to have Smith-Fineman-Myers syndrome (Villard et al., Am J Med Genet 91:83, 2000). Martinez et al. (J Med Genet 35:284, 1998) described a family with a phenotype similar to Sutherland-Haan syndrome, and Lossi et al. (Am J Hum Genet 65:558, 1999) have described a missense mutation in that family. Friez et al. (unpublished) have found a mutation in the XLID-arch fingerprints-hypotonia syndrome (Stevenson et al. J Med Genet 34:465, 1997). These findings confirm that a number of named XLID syndromes are allelic. Mutations have also been described in families with sufficiently mild expression to be considered nonsyndromal (Guerrini et al., Ann Neurol 47:117, 2000; Yntema et al., Am J Med Genet 110:243, 2002). Gibbons et al. (Hum Mutat 29:796, 2008) reviewed 127 mutations, the genotype-phenotype correlations, and other aspects of the ATR-X syndrome. Partial duplications of ATRX which result in decreased expression have also been found to cause the XLID-hypotonic facies phenotype (Thienpont et al., Eur J Hum Genet 15:1094, 2007).
• BCOR: Mutations in the BCL6 receptor gene, BCOR, have been found in one form of Lenz microphthalmia with associated anomalies (MAA2) and in families with OFCD (Ng et al., Nat Genet 36:411, 2004).
• BRWD3: Field et al. (Am J Hum Genet 81:367, 2007) reported two families with truncating mutations in BRWD3 (Xq21.1). Affected males had mild to moderate ID, macrocephaly, prominent forehead and large cupped ears.
• CASK: Piluso et al. (13th Workshop on Fragile X and XLID: p58, 2007) reported a missense mutation of uncertain significance in CASK (Xp11.4-p11.3) in a family with features of FG syndrome, and called FGS4 (Hum Genet 12:124, 2003). Najm et al. (Nat Genet online Aug 10, 2008) reported loss of function mutations in four girls and a splice mutation in one boy with severe ID, microcephaly, and disproportionately small brain stem and cerebellum. The gene has been deleted in contiguous gene deletions as well (Hayashi et al., Am M Jed Genet 146A: 2145, 2008; Froyen et al., Hum Mutat 28:1034, 2007).
• CDKL5 (STK9): The Serine-Threonine Kinase 9 gene, which is located in Xp22, distal to ARX, has been implicated as a second X-linked gene associated with severe intellectual disability and infantile spasms based on 2 females with X:autosome translocations that disrupt the gene (Kalscheuer et al., Am J Hum Genet 72:1401, 2003). Mutations have been identified in females with atypical Rett syndrome and early onset seizures who were negative for MECP2 mutations. Weaving et al. (Am J Hum Genet 75:1079, 2004), Tao et al. (Am J Hum Genet 75:1149, 2004), Scala et al. (J Med Genet 42:103, 2005, and Evans et al. (Eur J Hum Genet 13:1113, 2005) have reported deletion, missense and splice -site mutations in males and females with intellectual disability, seizures and clinical findings overlapping those of Rett and Angelman syndromes. Nemos et al. (Clin Genet 76:357, 2009) reported 5 missense, 4 splice site, a bp insertion and a 5' deletion among 137 females with early onset intractable seizures and hypotonia. They reviewed the 48 gene mutations reported to date. A milder later onset seizure disorder has been associated with a truncating mutation in the last exon (Psoni et al. Eur J Paediatr Neurol 14:188, 2010). Deletions of the CDKL5 gene have been reported in girls with early onset seizures and a Rett-like phenotype by Mei et al. (Epilepsia 51:647, 2010).
• CUL4B: Tarpey et al. (Am J Hum Genet 80:345, 2007) described three truncating, two splice site, and three missense mutations in the CUL4B gene (Xq24) in eight families with XLID, hypogonadism, short stature, obesity, behavioral outbursts and tremor. The families included the one reported by Cabezas et al. (J Med Genet 37:663, 2000). The gene encodes an E3 ubiquitin ligase (Zou et al., Am J Hum Genet 80:561, 2007).
• DLG3: Tarpey et al. (Am J Hum Genet 75:318, 2004) reported four truncating mutations in DLG3 in families with nonsyndromal XLID. A mutation has also been found in MRX8 (Schwartz, unpublished)
• FACL4: Meloni et al. (Nat Genet 30:1, 2002) reported finding mutations in 2 nonsyndromal XLID families in the fatty acid-CoA ligase 4 (FACL4) gene located in Xq22. One mutation was a missense (R570S) in the signature motif of fatty acyl-CoA synthesis. The second mutation was 1003-2A→C which resulted in a cryptic site being used at the 3’ end of intron 10 and the inclusion of 28 novel amino acids with an inframe stop codon. All female carriers exhibited highly skewed X-inactivation. The identification of FACL4 mutations in MRX males suggests normal lipid homeostasis is crucial for development and cognitive function. MRX63 and 68 have been found to have mutations in FACL4 (Meloni et al., Nat Genet 30:1, 2002; Longo et al., J Med Genet 40:11, 2003).
• FANCB: Holden et al. (J Med Genet 43:750, 2006) reported a truncating mutation in FANCB in a three generation family with X-linked VACTERL-hydrocephaly (Xp22.3). Female carriers showed markedly skewed X-inactivation.
• FGD1: A missense mutation (C935T) in the FDG1 gene has been described in three males with intellectual disability, but without the usual features of Aarskog syndrome (Lebel et al. Clin Genet 61:139-145, 2002).
• FLN1 (AKA FLNA): Mutations in the filamin-1 gene have been described in females and males with periventricular nodular heterotopia (Fox et al., Neurology 44:51, 1998; Sheen et al., Hum Mol Genet 10:1775, 2001). This large gene (48 exons) is located in Xq28. Mutations have been described in both familial and sporadic cases. Mutations in several males indicate that not all mutations are male-lethal. Robertson et al. (Nat Genet 33:487, 2003) have reported missense mutations in FLN1/FLNA in 10 individuals with otopalatodigital syndrome 2 (also called cranioorodigital syndrome, OPD2). Mutations were also reported in patients with OPD1, frontometaphyseal dysplasia, and Melnick-Needles syndrome. Mutations in FLNA have also been reported in males with some features of FG syndrome (Unger et al., Am J Med Genet 143:1876, 2007; Hehr et al., J Med Genet 43:541, 2006). This may possibly represent the so-called FGS2 locus.
• FTSJ1: The human homolog, E.coli FTSJ1 methyltransferase, located in Xp11.23 was found to have a mutation in MRX44 as well as two other families with non-syndromal XLID (Freude et al., Am J Hum Genet 75:305, 2004). Subsequently, Ramser et al. (J Med Genet 41:679, 2004) published a splice mutation in MRX9 and Takano et al. (Am J Med Genet 147B:479, 2008) a splice site mutation in another nonsyndromal XLID family.
• GRIA3: Chiyonobu et al. (Am J Med Genet 143A:1448, 2007) reported a partial tandem duplication of GRIA3 (Xq25) in a boy with marked delay of developmental milestones, short stature, hypertelorism, epicanthus and short neck. The mother, a carrier, showed markedly skewed X-inactivation. Bonnet et al. (Am J Med Genet 149A:1280, 2009) reported a partial duplication in brothers with ID, height and OFC in high centiles, and minor dysmorphism. The mother carried the duplication and had ID. A normal sister had the duplication and marked skewing of X-inactivation. GRIA3 had been previously identified as an ID candidate gene by Gecz et al. who reported a female with ID and bipolar disease who carried an X:12 translocation that disrupted the gene (Genomics 62:356, 1999). Wu et al. (PNAS 104:18163, 2007) sequenced GRIA3 in 400 males with XLID and found one gene deletion and four missense mutations.
• HADH2: Lenski et al. (Am J Hum Genet 80:372, 2007) reported a silent C→A transversion in exon 5 of the HADH2 gene in a family with MRXS10 (mild intellectual disability, choreoathetosis and abnormal behavior). The C→A substitution caused aberrant splicing of exon 5 resulting in reduced wild type transcript and the presence of a transcript lacking exon 5.
• HCCS: Wimplinger et al. (Am J Hum Genet 79:878, 2006) reported a missense mutation and a nonsense mutation in two females with MIDAS (microphthalmia-dermal aplasia-sclerocornea, MLS) syndrome who had normal chromosome analysis. They also found a deletion of part of the HCCS gene in a mother and two daughters with atypical findings. The gene encodes a mitochondrial holocytochrome c-type synthase. Affected girls tended to have marked skewing of X-inactivation.
• HUWE1: Froyen et al. (Am J Hum Genet 82:432, 2008) reported six families with duplications of Xp11.22 which contained three genes (RIBC1, HSD17B10, and HUWE1). The males appeared nonsyndromal although individual males had craniofacial, neuromuscular and behavioral manifestations. MRX17 and MRX31 were among the affected families. Three additional families including the XLID-macrocephaly syndrome had missense mutations of HUWE1. Juberg-Marsidi and Brooks syndromes have missense mutations in HUWE1 (Schwartz, personal communication). They are quite similar clinically and distinctly different from nonsyndromal XLID and XLID-macrocephaly syndrome. One of the families with a missense mutation (UK106) reported by Froyen et al. (2008) appears clinically similar as well.
• IAP (MAGT1): Molinari et al. (Am J Hum Genet 82:1150, 2008) described a missense mutation (p.V311G) in the IAP gene in Xq21.1 in a family with nonsyndromal XLID. Mild cognitive impairment was noted in carrier females. The gene encodes a subunit of an oligosaccharide transferase which is involved in N-glycosylation.
• IGBP1: Graham et al. (Am J Med Genet 123A:37, 2003) reported alterations of uncertain significance in the IGBP1 gene in two brothers with agenesis of the corpus callosum, ocular coloboma, and micrognathia.
• IL1RAPL1: The IL-1 receptor accessory protein (IL1RAPL1), located in Xp22.1, was found to be deleted in males from family MRX34. A nonsense mutation (G1377A), creating a stop codon at amino acid 459, was identified in a previously unreported MRX family (Carrie et al., Nat Genet 23:25, 1999). A second male patient has been identified with an IL1RAPL disruption and ID (Bhat et al., Am Soc Hum Genet Meeting, 2005). A truncating mutation was found in MRX21 by Tabolacci et al. (Am J Med Genet 140:482, 2006). Inversions and deletions involving IL1RAPL1 have been reported by Lepretre et al. (Cytogenet Genome Res 101:124, 2003), Billuart et al. (Hum Mol Genet 5:977, 1996), des Portes et al. (Clin Genet 53:136, 1998), and others. Nawara et al. (Am J Med Genet 146:3167, 2008) reported a partial deletion of IL1RAPL1 in a family with four males with nonsyndromal XLID.
• IQSEC2: Mutations in this guanine nucleotide exchange factor gene, located in Xp11.2, have been reported in four nonsyndromal XLID families including MRX1 and MRX18 by Shoubridge et al. (Nat Genet 42:486, 2010).
• JARID1C (KDM5C, SMX): Jensen et al. (Am J Hum Genet 76:227, 2005) reported frameshift, nonsense, and missense mutations in JARID1C (Xp11.2) in affected males with variable growth and craniofacial, neurological, behavioral and other abnormalities from seven families. Mental impairment was variable as well. Some cases were considered nonsyndromal. Carrier females appeared normal. Tzschach et al. (Hum Mutat 27:389, 2006) reported one nonsense and four missense mutations in 5 families in which males had variable phenotype. An additional missense mutation was reported in two brothers with severe ID (Santos et al., Eur J Hum Genet 14:583, 2006). Abidi et al. (J Med Genet 45:787, 2008) observed that JARID1C mutations are associated with short stature and hyperreflexia as well as ID.
• KDM5C (see JARID1C)
• KIAA1202: Hagens et al. (Hum Genet 118:578, 2006) reported disruption of the KIAA1202 gene in two females with X:autosome translocations and a missense mutation in the Stocco dos Santos syndrome (severe ID, delayed/absent speech, seizures and hyperactivity).
• KIAA2022: Cantagrel et al. (J Med Genet 41:736, 2004) described a pericentric inversion of the X chromosome in two related males with short stature, severe intellectual disability, hypotonia, seizures, spastic quadriplegia, hydrocephalus, absence of language, gastrointestinal reflux, and abnormal movements. One of the inversion breakpoints interrupted KIAA2022 (Xq13.2). No mutations were found in 20 other linked families.
• KLF8/ZNF741: Lossi et al. (J Med Genet 39:113, 2002) reported abnormal expression of KLF8 in a female with an X:21 translocation and nonsyndromal XLID.
• LAMP2: Mutations in the gene encoding lysosome-associated membrane protein 2 (Xq24) causes Danon Disease (X-linked vacuolar cardiomyopathy and myopathy). In addition to the cardiomyopathy, intellectual disability of variable degree occurs in most affected males (Sugie et al. Neurol 58:1773, 2002; Nishino et al. Nature 406:906, 2000; Balmer et al., Eur J Ped 164:509, 2005; Yang et al., Circulation 112:1612, 2005). Spinazzi et al. (Clin Genet 73:388, 2008) and van der Kooi et al. (Neurology 70:1358, 2008) have discussed natural history.
• MAGT1 (IAP): Molinari et al. (Am J Hum Genet 82:1150, 2008) reported a missense mutation of MAGT1 in one family with males with severe intellectual disability and female carriers with mild cognitive disability. The gene encodes a subunit of an oligosaccharyltransferase involved in N-glycosylation.
• MBTPS2: Oeffner et al. (Am J Hum Genet 84:459, 2009) reported missense mutation in the intramembrane zinc metalloprotease gene, MBTPS2, in five unrelated patients with IFAP (ichthyosis follicularis, atrichia, photophobia) syndrome. The gene is located in Xp22.1. Other missense mutations are known (C. Schwartz, A. Kline, P. Tarpey, personal communication, April 2009).
• MCT8 (SLC16A2): Friesema et al. (Lancet 364:1435, 2004) reported two deletions and three missense mutations in five unrelated males with severe intellectual disability, hypotonia, lack of speech and involuntary movements. T3 was elevated but no signs of thyroid dysfunction were present. Serum free and total T4 were low or low normal and serum TSH was normal to elevated. Dumitrescu et al. (Am J Hum Genet 74:168, 2004) reported two similarly affected children with MCT8 mutations. Schwartz et al. (Am J Hum Genet 77:41, 2005) reported mutations and thyroid function disturbances in six families with Allan-Herndon-Dudley syndrome. Holden et al. (J Child Neurol 20:852, 2005), Maranduba et al. (J Med Genet 43:457, 2006), Jansen et al. (J Clin Endocrinol Metab 92:2378, 2007), and Frints et al. (Eur J Hum Genet 16:1029, 2008) published additional AHDS families with MCT8 mutations. One female affected with clinical and hormonal changes of AHDS was found to have MCT8 interrupted by an X:9 translocation (Eur J Hum Genet 16:1029, 2008). Wemeau et al. (J Clin Endocrinol Metab 93:2084, 2008) noted somatic but not psychomotor improvement with PTU and T4 treatment.
• MECP2: The methyl-CpG binding protein (MECP2), known to be involved in Rett syndrome, was found to also be responsible for some forms of XLID. Orrico et al. (FEBS Letters 24106:1, 2000) found an A140V mutation in a family in which both males and females had ID. The affected female proband had microcephaly, an asthenic habitus, speech problems, genu valgum and an unsteady gait. Meloni et al. (Am J Hum Genet 67:982, 2000) found a G406X mutation in an XLID family previously reported by Claes et al. (Clin Genet 52:155, 1997). The phenotype consisted of severe ID associated with progressive spasticity. They also had facial hypotonia and sialorrhea, with head circumferences in the 75th-90th percentile. Of particular interest, the obligate carriers were not affected even though they did not exhibit skewed X-inactivation as would be expected. Couvert et al. (Hum Mol Genet 15:941, 2002) reported finding a MECP2 mutation (E137G) in MRX16 and another mutation, R167W, in a second XLID family linked to Xq28. Furthermore, the authors screened 185 fragile X negative males and found two A140V mutations, a P399L mutation and a R453Q mutation. Based on these latter results, it was suggested that MECP2 mutations may occur at a relatively high (about 2%) frequency in the male ID population. However, other publications (Moncla et al., Eur J Hum Genet 10:86, 2002; Yntema et al. Am J Hum Genet 69:A632, 2001) raise the distinct possibility that many mutations in MECP2 observed in males may actually be rare polymorphisms. Thus, caution must be taken in interpreting MECP2 alterations. A mutation in MECP2, A140V, was found in a family with PPM-X (psychosis, pyramidal signs and macroorchidism) (MIM 300055; Klauck et al., Am J Hum Genet 70:1034, 2002). This same mutation has been observed in other patients including the family with MRX79 (Orrico et al., FEBS Lett 481:1034-1037, 2000; Couvert et al., Hum Mol Genet 10:941-946, 2001; Winnepenninckx et al., Hum Mutat 20:249, 2002). Thus, the authors raise the possibility this particular amino acid, A140, is a mutation hot-spot in MECP2. However, even this possibility must be approached with caution since another study of 525 males with non-Fragile X ID failed to detect the A140V variant (Lobo-Menendez et al., Am J Hum Genet 73(Suppl):537, 2003). Recent findings indicate that duplication of a region of Xq28, which includes MECP2, gives rise to severe ID plus other features (spasticity, hypotonia, recurrent infections) (van Esch et al., Am J Hum Genet 77:442, 2005). The family published by Lubs et al. (Am J Med Genet 85:243, 1999) as XLID-hypotonia-recurrent infections, the family published by Pai et al. (J Med Genet 34:529, 1997) as a new XLID syndrome, and five other clinically similar families are also found to have a duplication of this region (Friez et al., Pediatrics 118:e1687, 2006). Carriers show marked skewing of X-inactivation. Del Gardio et al. (Genet Med 8:784, 2006) and Smyk et al. (Am J Med Genet B Neuropsychiatr Genet 147B:179, 2008) have reported other cases. Lugtenberg et al. (Eur J Hum Genet: Nov 5, 2008 - epub ahead of print) found MECP2 duplications in 1% of unexplained XLID and 2% of those with severe ID and progressive neurological symptoms.
• MED12 (HOPA/TRAP230): Risheg et al. (Nat Genet 39:451, 2007) have found a p.R961W mutation in the MED12 gene (Xq12) in five families including the original family with FG syndrome. The gene is a component of one module of the Mediator Complex, which is required for activation and suppression of transcription by RNA polymerase II. More recently, Schwartz et al. (J Med Genet 44:472, 2007) have reported a different mutation (p.N1007S) in the original Lujan syndrome family. Clinical reports of cases with mutations have been made by Lyons et al., J Med Genet 46:9, 2009 and Graham et al., Am J Med Genet 146:3011, 2008. Clark et al. (Genet Med 11:769, 2009) summarized the clinical findings in all cases with the R961W mutation and proposed an algorithm for diagnostic testing.
• MID1: A variety of alterations in a RING finger gene on Xp22 have been demonstrated in patients with hypertelorism-hypospadias (Opitz BBB, Opitz G) syndrome (Quaderi et al., Nat Genet 17:285, 1997; Winter et al., Hum Genet 112:249, 2003).
• NDUFA1: Fernandez-Moreira et al. (Ann Neurol 61:73, 2007) found mutations in the NDUFA1 gene in males with mitochondrial encephalomyopathy (mitochondrial complex I deficiency). The gene locus is in Xq24.
• NHS: Burdon et al. (Am J Hum Genet 73:1120, 2003) reported truncating mutations in 5 families with Nance-Horan syndrome. The gene is located in Xp22.13. It is a novel gene which appears to have a complex pattern of expression, during development, in multiple organs.
• NLGN3: This member of the neuroligin family located in Xq13 has been implicated as a possible cause of autism (Soderstrom et al., Nat Genet 34:27, 2003).
• NLGN4 (KIAA1260): A frameshift mutation in this member of the neuroligin family located in Xp22.3 has been reported in 2 brothers, one with autism, the other with Asperger syndrome (Soderstrom et al., Nat Genet 34:27, 2003). Laumonnier et al. (Am J Hum Genet 74:552, 2004) reported a truncating mutation in NLGN4 in an MRX family as well as sequence variations in 5 unrelated patients with autism. The role of NLGN4 in autism appears to be complex. One study found mutations in a cohort of patients with autism at a frequency of about 2% (Yan et al., Mol Psychiatry 10:329, 2005). However, three other studies conducted in patients with autism found no NLGN4 mutations (Vincent et al., Am J Med Genet B Neuropsychiatr Genet 129:82, 2004; Gauthier, Am J Med Genet B Neuropsychiatr Genet 132:74, 2005; Ylisaukko-oja et al., Eur J Hum Genet 13:1285, 2005). Lawson-Yuen et al. (Eur J Hum Genet 16:614, 2008) reported an intragenic deletion in NLGN4 associated with a wide spectrum of neurospychiatric disorders in one family.
• NSDHL: van Allen et al. (David W. Smith Workshop on Malformations and Morphogenesis, Philadelphia, August 2009; du Souich et al., Am J Med Genet 149A:2469, 2009) reported a 3 bp deletion in this NAD(P)H steroid dehydrogenase-like gene in an XLID family (7 affected males) with microcephaly, pachygyria, variable ID, long narrow face, almond-shaped eyes, high nasal bridge and palate, ocular abnormalities, skeletal abnormalities, seizures, hypotonia, ID and behavioral disturbances including autism. Mutations in this gene have previously been associated with CHILD syndrome.
• OFD1: Mutations in the gene for Oral-Facial-Digital I syndrome localized in Xp22 have been described by Ferrante et al. (Am J Hum Genet 68:569, 2001). Budney et al. (Human Genet 120:171, 2006) described a family with frameshift mutation in OFD1 which was associated with severe ID, macrocephaly and recurrent respiratory infections. Affected males died in infancy; carrier females did not appear abnormal.
• OPHN1: Mutations have been demonstrated in this Rho-GTPase activating protein in MRX60 (Billuart et al., Nature 392:923, 1998), in a family with XLID, epilepsy, and cerebellar hypoplasia (Bergmann et al., Brain 126:1537, 2003) and in 2 other XLID families with cerebellar hypoplasia (Philip et al., J Med Genet 40:441, 2003). Bedeschi et al. (Am J Med Genet 146:1718, 2008) reported an 800 bp duplication of Xq12-q13.1, which includes OPHN1, YIPF6 and STARD8. The affected male had dysmorphic facies, scoliosis and severe ID. Functionally, the OPHN1 protein is required for dendritic spine morphogenesis (Govek et al., Nat Neurosicence 7:364, 2004). OPHN1 forms a complex with Endophilin A1 and plays a role in synaptic vesicle endocytosis (Nakano-Kobayashi et al. Cur Biol 19:1, 2009). A role in controlling synapse maturation and plasticity by stabilizing AMPA receptors has been reported by Kasri et al. (Gen and Dev 23:1289, 2009).
• PAK3: A novel missense mutation (R67C) was identified in MRX30 and MRX47 (Allen et al., Nat Genet 20:25, 1998; Bienvenu et al., Am J Med Genet 93:294, 2000). A missense mutation (c1094A) has also been found in a large MRX family by Gedeon et al. (Am J Med Genet 120A:509, 2003).
• PCDH19: Dibbens et al. (Nat Genet 40:776, 2008) have found mutations in the protocadherin 19 gene in seven families with epilepsy and intellectual disability limited to females (EIDF). The gene is in Xq22. Scheffer et al. (Brain 131:918, 2008) reported the clinical findings separately. The absence of findings (epilepsy and ID) in males, they propose, is due to rescue by a protocadherin gene (PCDH11Y) on the Y chromosome. Other families have been reported by Depienne et al. (PLoS Genet 5;2009, e1000381) and Hynes et al. (J Med Genet 47:211, 2010).
• PHF6: Mutations in the PHF-like zinc finger gene 6P have been described in the Borjeson-Forssman-Lehmann syndrome (Lower et al., Nat Genet 32:661, 2002). Lower et al. (Eur J Hum Genet 12:787, 2004) identified a nonsense mutation (R342X) in the original BFL syndrome family. Other mutations have also been reported (Vallee et al., J Med Genet 41:778, 2004; Crawford et al., J Med Genet 43:238, 2006).
• PHF8: The XLID-cleft lip/palate syndrome (Siderius syndrome), which maps to Xp11, is due to a 12bp deletion in PHF8 (Laumonnier et al., J Med Genet 42:780, 2005). These authors also identified a PHF8 mutation in a second family with Siderius XLID syndrome. Abidi et al. (Clin Genet 72:11, 2007) found a truncating mutation in one individual in a cohort of 26 with ID and cleft lip/palate. The gene appears to be a histone demethylase which coactivates transcription (Fortschegger et al. Mol Cell Biol 30:3286, 2010).
• PQBP1: The polyglutamine tract binding protein 1 maps to Xp11.2 within the 7.3 Mb region in proximal Xp found to be rich in localizations for MRX genes (Ropers et al., Trends Genet 19:316, 2003). Mutations which alter the number of (AG) repeats in exon 5 have been demonstrated in MRX55, in Sutherland-Haan syndrome, in Hamel syndrome, and in two other families with microcephaly and other anomalies (Kalscheuer et al., Nat Genet 35:313, 2003). Different truncating mutations have been found in the original Renpenning syndrome family, in another XLID family with microcephaly and short stature (Lenski et al., Am J Hum Genet 74:777, 2004), and in the Porteous syndrome (Stevenson et al., Am J Med Genet 134A:415, 2005). The first missense mutation (c.194 A→G) in PQBP1 has been identified in the Golabi-Ito-Hall family (Lubs et al., J Med Genet 43:e30, 2006).
• PRPS1: Mutations in the phosphoribosyl pyrophosphate synthetase 1 gene were described in patients with Arts syndrome (ID, hypotonia, ataxia, hearing loss, optic atrophy) by deBrouwer et al. (Am J Hum Genet 81:507, 2007). Some families in which phosphoribosylpyrophosphate synthetase 1 superactivity has occurred have shown deafness, developmental delay, and neurologic signs in males (Christen et al., Lancet 340:1167, 1992).
• PTCHD1: Noor et al. (Sci Transl Med 2:49ra68, 2010) identified both deletions and missense mutations in the PTCHD1 gene in males with either autism spectrum disorder (ASD) or intellectual disability. Overall, 3/225 males (1.6%) with ID who had been analyzed for both CNV and sequence variants had PTCHD1 mutations and 4/353 (1.1%) similarly studied probands with ASD had PTCHD1 mutations. Additionally, deletions of the 5' region of PTCDH1 were found in 8/996 (.8%) of patients with ASD. This implies that PTHCD1 may account for about 1% of individuals with ASD and ID.
• RAB39B: One truncating mutation and one splice site mutation were found in this small GTPase gene in Xq28 by Giannandrea et al. (Am J Hum Genet 86:185, 2010). The splice site mutation was found in MRX72 and the truncating mutation in six males with macrocephaly and variable stature, intellectual disability, and autism.

• RAB40AL. Missense mutations in this gene have been found in the family reported by Martin et al. (J. Med Genet 37:836, 2000) and in one sporadic case (Int Congress Hum Genet, Montreal, October 2011).

• RPSKA3, RSK2: The serine-threonine protein kinase (RSK2), known to be involved in the Coffin-Lowry syndrome (CLS), was shown to also be responsible for MRX19 (Merienne et al. Nat Genet 22:13, 1999). A missense mutation (C1147T) in exon 14 resulted in decreased kinase activity, which is presumed to be the cause of the ID observed in MRX19. Delaunoy et al. (Clin Genet 70:161, 2006) reported 44 novel mutations and state that of the 128 mutations now known, 15% are nonsense, 29% deletions or insertions, 20% splicing, and 33% missense. Pereira et al. (Hum Genet 122:541, 2007) reported a large intragenic duplication in one patient. The majority of mutations have been found in only one family, two-thirds of mutations are de novo, and, in most families (60%) referred for testing, no mutation was found.

• SIZN2: One mutation (c.1031C→T, p.T344I) which segregated in an XLID family and a second mutation (c.19C→T, p.R7C) found in 4/290 black males with ID was reported by Srivastava et al. (12th International Fragile X/XLMR Workshop, Williamsburg, VA 2005). Additional p.R7C mutations have been found in an additional cohort of males with ID on unknown cause (Cho et al. Am J Med Genet A 146A:2644, 2008). Little clinical detail was provided.
• SLC6A8: A nonsense mutation (R514X) in the creatine transporter gene located in Xq28 has been described in a seven year old boy with mild intellectual disability and two female relatives by Salomons et al. (Am J Hum Genet 68:1497, 2001). A second family in which five males and two females are affected have been found to have a missense mutation (G1141C) which leads to a glycine being replaced by an arginine and also alternative splicing (Hahn et al., Am J Hum Genet 70:1349, 2002). Affected males have increased creatine in plasma and urine, which may serve as an easy biochemical screening method. Other cases have been recognized by several research centers using urine creatine, magnetic resonance spectroscopy and mutation detection strategies. Seven families with SLC6A8 mutations have been summarized in the literature (Salomons et al., J Inherit Metab Dis 26:309, 2002). Additionally, Rosenberg et al. (Am J Hum Genet 75:97, 2004) found a prevalence of SLC6A8 mutations of 2% in the XLID population. Clark et al. (Hum Genet 119:604, 2006) found a lower prevalence (1%) in males with ID of unknown cause.
• SLC9A6: Mutations in the sodium-hydrogen exchanger NHE6 gene (Xq26.3) were reported by Gilfillan et al. (Am J Hum Genet 82:1, 2008) in four families in which males had an Angelman-like syndrome with ID, microcephaly, epilepsy, ataxia and absent speech. One of the families had been previously published and recognized as Christianson syndrome (J Med Genet 36:759, 1999). Additional families have been identified by Schroer et al. (Am J Med Genet, Epub ahead of Print Oct. 14, 2010).
• SMC1L1 and SMC3L1: Musio et al. (Nat Genet 38:528, 2006) reported mutations in SMC1L1 (Xp11.2) in three males in one family and one male in a second family with Cornelia de Lange syndrome. These cases were among the 33 of 53 CdLS patients that are negative for mutations in NIPBL. Both genes are components of the cohesion complex. Deardorf et al. (Am J Hum Genet 80:485, 2007) have recently reported additional SMC1L1 mutations and one mutation in SMC3L1.
• SMS: A mutation in the spermine synthase gene has been found in the family designated Snyder-Robinson syndrome (Snyder and Robinson, Clin Pediatr 8:669, 1969; Arena et al., Am J Med Genet 64:50, 1996; Cason et al., Eur J Hum Genet 11:937, 2003). Spermine synthase activity is markedly reduced in lymphocytes and fibroblasts and the spermidine:spermine ratio elevated. Alencastro et al. (J Med Genet 45:539, 2008) reported a second mutation (missense in the N-terminal region) which causes severe intellectual disability and seizures. Becerra-Solano et al. (Am J Med Genet A 149A:328, 2009) reported a third mutation (missense) in exon 5 which causes intellectual disability, osteoporosis, multiple fractures and facial asymmetry. Schwartz (personal communication) has identified a fourth mutation (missense).
• SMX (see JARID1C)
• SOX3: Laumonnier et al. (Am J Hum Genet 71:1450, 2002) have described mutations in SOX3 in the XLID-growth hormone deficiency syndrome (Hamel et al., Am J Med Genet 64:35, 1996).
• SRPX2: Missense mutation in the Sushi repeat containing protein, X linked 2 (Xq22.1) segregated with intellectual disability, Rolandic epilepsy and speech dyspraxia in a three generation family. A second missense mutation was found in a 15-year-old boy with Rolandic epilepsy and bilateral perisylvian polymicrogyria (Roll et al. Hum Mol Genet 15:1195, 2006).
• STK9 (see CDKL5)
• SYN1: Garcia et al. (J Med Genet 41:183, 2004) identified a nonsense mutation (W356X) in SYN1 in a family with epilepsy, learning problems and behavior disorders. Not all males with the mutation had ID and behavioral difficulties.
• TM4SF2 / TSPAN7: The transmembrane 4 superfamily member 2 gene (TM4SF2), located in Xp11.4, was found to be disrupted by an X:2 balanced translocation in a female patient with mild ID plus minor autistic features (Zemni et al., Nat Genet 24:167, 2000, de Vos et al., Genetic Counseling 13:191, 2002). Two additional mutations (G128X and P172H) were found in two unrelated families with XLID (ibid). Subsequent study has indicated that one of the substitutions may represent a polymorphism (Gomot et al., Am J Med Genet 112:400, 2002). Abidi et al. (J Med Genet 39:430, 2002) reported MRX58 resulted from a 2 bp deletion (564delGT) in TM4SF2, which results in a stop codon six amino acids later at amino acid 186 (FS186X). This leads to truncation of the protein. A partial duplication that did not interrupt TM4SF2 expression was found in a boy with autism and his unaffected mother by Noor et al. (Psychiat Gen 19:154, 2009).
• UBE2A: Nascimento et al. (Am J Hum Genet 79:549, 2006) found mutations in the ubiquitin conjugating enzyme (Xq24-25) in three males with facial dysmorphism, short wide neck with low hairline, widely spaced nipples, small penis, ectodermal findings (dry skin, hirsutism, nail dystrophy, seizures), and speech impairment. Carriers showed marked skewing of X-inactivation. Budny et al. (Clin Genet 77:541, 2010) has reported two additional families with missense mutations.
• UPF3B: Mutations in UPF3B (Xq24-q25), a member of the nonsense mediated decay complex, were found in four families - one with FG phenotype, two with Lujan phenotype, and one with nonsyndromal XLID by Tarpey et al. (Nat Genet 39:1127, 2007). The three truncating mutations produced syndromic phenotypes; the missense mutation produced nonsyndromal XLID. Laumonnier et al. (Mol Psychiatry 2009 Feb 24 Epub ahead of print) reported a nonsense mutation in MRX62 and missense mutations in two families with ID with or without autism.
• XNP (See ATRX)
• ZDHHC9: Raymond et al. reported frameshift, missense, and splice site mutations in the palmitoyltransferase gene (Xq26.4) in males with moderate ID, some of which had macrocephaly and Marfanoid habitus (Am J Hum Genet 80:982, 2007).
• ZDHHC15: Mansouri et al. (Eur J Hum Genet 13:970, 2005) found the absence of ZDHHC15 transcripts in a female with an X:15 (q13.3:cen) translocation. The patient had intellectual disability and seizures.
• ZNF41: This gene was disrupted in a patient with an X:7 translocation (Shoichet, Am J Hum Genet 73:1341, 2003). Two other possible disease-causing mutations were found in MRX patients.
• ZNF674: Lugtenberg et al. (Am J Hum Genet 78:265, 2006) reported a contiguous gene deletion spanning 5 genes in Xp11.3 including the zinc finger gene, ZNF674, in a boy with learning disability, retinal dystrophy, and short stature. Mutational analysis in 28 families with nonsyndromal XLID linked to the region found one nonsense mutation and study of 306 other males with XLID detected two missense mutations, one of which is likely disease-causing.
• ZNF81: This gene was found at the Xp11.23 breakpoint in a female with intellectual disability and an X:9 translocation. A missense mutation has been found in MRX45 (Kleefstra et al., J Med Genet 41:394, 2004).

Duplication of XLID Genes and Regions of the X Chromosome Genome

Segmental duplications involving one or more genes on the X chromosome have been associated with intellectual disability. In some instances it is unclear whether the whole gene duplication, partial duplication of adjacent gene(s), or other position effect is most important in the causation of ID. In many cases of clinically important segmental duplications of the X chromosome, marked skewing of X-inactivation has been documented in carrier females.

• Xp22.31. Wagenstaller et al. (Am J Hum Genet 81:738, 2007) reported a 1.4 Mb duplication in a boy with severe language delay and acquired microcephaly. The duplicated genes were VCX3A, HDHD1A, STS, VCX, PNPLA4, and VCX2. The healthy mother carried the duplication. Horn et al. (Mediz Genetik 19:62, 2007) reported similar duplications in two unrelated males with ID: one with ID and “autistic aggressive” behavior, the other with ID, hypotonia, overgrowth, hypertelorism, bifid nasal tip, long philtrum, and aggressive behavior.
• Xp22.2-p21.3. Two families with 69 kb duplications including REPS2, NHS, and ILRAPL1 were reported by Honda et al. (J Hum Genet 55:590, 2010). The clinical findings appeared different in the two families. In the first family, a male had severe ID, infantile spasms, absent speech and atrophy of the hippocampus. In the other family, twin boys had moderate ID, speech delay and autistic features.
• Xp22.13-p22.11. A 12.5 Mb duplication of Xp22.11-p22.13 which included AP1S2, CDKL5, SCML1, PDAA1, RPS6KAS, SMX, and ARX was found in two brothers with moderate ID, hypotonia, seizures, submucus cleft palate, long face with flat midface, asthenic habitus, scoliosis and long digits (Gijsbers et al. Clin Genet 2010. Epub ahead of print). A 3.8 Mb duplication that includes RPS6KA3, MBTDS2 and SMS in one family with nonsyndromal XLID was reported by Whibley et al. (Am J Hum Genet 87:173, 2010).
• Xp21.3. A 41 kb duplication that includes ARX and POLA1 (partial) has been found in one family with nonsyndromal XLID (Whibley et al. Am J Hum Genet 87:173, 2010).
• Xp11.3-p11.23. A number of duplications, varying in size from 0.8 - 9.2 Mb, have been reported in this region (Froyen et al. Hum Mut 28:1034, 2007; Bonnet et al. J Hum Genet 51:815, 2006; Marshall et al. Am J Hum Genet 82:427, 2008; Giorda et al. Am J Hum Genet 85:394, 2009; El-Hattab et al. Clin Genet 2010 June 29 [Epub ahead of print]. Clinical findings in the 11 families and four males with these duplications show the severity of intellectual disability has varied widely as have stature, head circumference, and facial dysmorphism. A minority have had deformation of the lower limbs, hypotonia, seizures and autistic features.
• Xp11.22. Froyen et al. (Am J Hum Genet 82:432, 2008) reported variable length duplications in Xp11.22 in six families with nonsyndromal XLID, including MRX17 and MRX31. The duplications ranged in size from about 300 kb to about 800 kb. Three genes were included in the common region of duplication: RIBC1, HSD17B10 and HUWE1. Duplication of RIBC1 was excluded as a cause of ID since it is not brain expressed. Missense mutations in HUWE1 were also found in three additional families with XLID. Four additional families with nonsyndromal XLID with 400-1000 kb duplications of this region were reported by Whibley et al. (Am J Hum Genet 87:373, 2010). Honda et al. (J Hum Genet 55:590, 2010) reported a 1.37 Mb duplicaton that included FTSJ1, PQBP1, and SYP in a male with speech delay and moderate ID. His sister was said to be affected, but details were not provided.
• Xq12-q13.1. An 800 kb duplication that includes OPHN1 was found in a 20 year old male with prenatal and postnatal undergrowth, global developmental delay, hypertelorism, deep-set eyes, downslanting palpebrae, narrow nasal bridge, broad nasal tip, long philtrum, thin upper lip, thick lower lip, cupped left ear, join laxity, truncal hypotonia, leg length asymmetry, muscular underdevelopment and hyperreflexia. MRI showed normal posterior fossa but abnormalities of corpus callosum, cerebral white matter, internal capsules and pontine tegmentum (Bedeschi et al. Am J Med Genet 146A:1718, 2008).
• Xq13.2-q21.1. A 7 Mb duplication in Xq13.2-q21.1 was found in a male with severe ID, growth retardation and facial dysmorphism by Koolen et al. (Hum Mutat 30:283, 2009). The duplication was de novo, but no other details were provided. An 11.5 Mb duplication of Xq13.1-q21.1 that includes MED12, NLGN3, SLC16A2, KIAA2022, ATRX, and BRWD3 in one family with syndromal XLID (Whibley et al. Am J Hum Genet 87:173, 2010).
• Xq21-q22. The most common segmental duplication on the X chromosome involves the PLP1 gene at Xq22 and is responsible for the majority of cases of Pelizaeus-Merzbacher disease (Mimault et al.: Am J Hum Genet 65:360, 1999). The duplications range in size from <200 - 1650 kb and affect adjacent genes since the PLP1 gene spans only 17 kb (Woodward et al.: Am J Hum Genet 63:207, 1998). The size of duplication has not been correlated with clinical severity of the disease (Regis et al.: Clin Genet 73:279 2008).
• Xq22.3. Jehee et al. (Am J Med Genet 139A:221, 2005) described a 4 Mb duplication in Xq22.3 in a male with cognitive disability, hypotonia, trigonocephaly (premature metopic closure), upslanted palpebrae, short nose, long philtrum, hypospadias, recurrent hyperthermia, and constipation. They considered the child to have FG syndrome and designated the Xq22.3 as FGS locus 5. We consider this diagnosis to be incorrect (Schwartz and Stevenson: David W. Smith Workshop on Malformations and Morphogenesis, Mont Tremblant, Ontario, August 2008).
• Xq24. A 190 Mb duplication in Xq24 was reported in a male with moderate ID, macrocephaly, facial dysmorphism, hypotonia, and pectus excavatum and his normal mother by Koolen et al. (Hum Mutat 30:283, 2009). The significance was unclear.
• Xq25. A de novo 255Kb duplication encompassing four known genes (BCORL1, ELF4, PDCD8 and RAB33A) was identified in a female with clinical features suggestive of Rett syndrome. The patient had skewed X-inactivation with the abnormal X being preferentially active based on expression studies of the genes involved. Further studies suggest that overexpression of PDCD8 and RAB33A are most likely involved in the etiology of the clinical features in this patient (D. Cohn, personal communication).
• Xq25-q26.3. A 4.7 Mb duplication was found in a male with moderate ID, growth retardation, microcephaly, cleft palate, hypospadias, and cryptorchidism and his normal mother by Koolen et al. (Hum Mutat 30:283, 2009). The significance was unclear.
• Xq27.2-q27.3. Several families in which males have had ID and panhypopituitarism have been found to have duplications in Xq27 (Lagerström-Fermér et al.: Am J Hum Genet 60:910, 1997, Hol et al.: Genomics 69:174, 2000, Laumonnier et al.: Am J Hum Genet 71:1450, 2002, Solomon et al.: J Med Genet 41:669, 2004). The duplication critical region appears to span a 3.9 Mb interval in Xq27.2-q27.3. The duplicated region contains SOX3, the transcription factor known to be associated with XLID-panhypopituitarism.
• Xq27.3-q28. A small duplication of about 5 Mb was identified in a family in which affected males had short stature, hypogonadism and some facial dysmorphism (deep-set eyes, bulbous nasal tip and thin lips) (Rio et al., Eur J Hum Genet 18:285, 2010). Some genes encompassed within the duplication are FMR1, AFF2, IDS and MTM.
• Xq28. Van Esch et al. (Am J Hum Genet 77:442, 2005), Friez et al. (Pediatrics 118:e1687, 2006), Lugtenberg et al. (Eur J Hum Genet 17:444, 2009), and others have reported a number of males with ID and duplications of variable size including and adjacent to MECP2. The phenotype includes severe cognitive disability (sometimes with autism or autistic manifestations), hypotonia, absent/limited speech, absent/limited ambulation, spasticity, seizures, and recurrent respiratory infections. Two previously described XLID entities – XLID-hypotonia-recurrent infections (Lubs et al.: Am J Hum Genet 85:243, 1999) and MRX64 (Pai et al.: J Med Genet 34:529, 1997) – are caused by this duplications. The duplications range in size from 0.3 to 2.3 Mb (Bauters et al.: Genome Res 18:847, 2008). The phenotype appears related primarily to duplications of MECP2 (Van Esch et al.: Am J Hum Genet 77:442, 2005, Meins et al.: J Med Genet 42:e12, 2005, Kirk et al.: Clin Genet 75:301, 2009, Velinou et al.: Clin Dysmorphol 18:9, 2008, Smyk et al.: Am J Med Genet B 147B:799, 2008). Clayton-Smith et al. (Eur J Hum Genet 17:434, 2009) described several families in which the duplication included SLC6A8 and FLNA. Affected males had intestinal pseudo-obstruction or bladder distension as additional findings. Rosenberg et al. (J Med Genet 43:180, 2006) reported a 1.3 Mb duplication in Xq28 in a male with ID, large ears, high palate, hypoplasia of cerebellar vermis, Dandy-Walker anomaly, abdominal obesity, and flat feet. An affected maternal cousin also had the duplication. Whibley et al. (Am J Hum Genet 87:173, 2010) report a 210 kb duplication that includes part of AFF2 in one family with nonsyndromal XLID.