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

New X-linked mental retardation syndromes, new gene localizations, revised gene localizations, and gene identifications are presented in abbreviated form with appropriate references.  Three graphics show gene localizations and linkage limits.

XLMR Update - July 2008

I.   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).

• Craniofacioskeletal syndrome. Stevenson et al. (Am J Med Genet 143:2321, 2007). Based on one family with seven females with mild MR, 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 XLMR, 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 mental retardation. 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.

• MRXS7 (Ahmad et al., Eur J Hum Gen 7:828, 1999). Based on a Pakistani family with 10 affected males showing mild to moderate MR, 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 MR, 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 XLMR syndrome with severe MR, 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 XLMR syndrome that resembled Joubert syndrome. A daughter also had severe mental retardation, but was not described further.

• X-linked Cornelia de Lange syndrome - See Section II for gene in Xp11.2.

• X-linked hypoparathyroidism. Usually leads to infantile hypocalcemia, hypophosphatemia, seizures and death in males; survivors may have cataracts, short stature and mental retardation. 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).

• XLMR-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).

• XLMR-choreoathetosis, MRXS10 (Reyniers et al., Am J Hum Genet 65:1406, 1999). Based on 5 affected males with mild MR, 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).

• XLMR-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 XLMR-coarse facies in Xq26-q27.

• XLMR-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:207, 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 mental retardation. A localization was not reported, although Xq28 was excluded and mutational analysis of the EBP gene was negative.

• XLMR-hypogonadism-tremor (Cabezas et al., J Med Genet 37:663, 2000). Based on 6 affected males in 3 generations showing severe MR, 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).

• XLMR-microcephaly-testicular failure. Cilliers et al. (Eur J Med Genet 50:216, 2007) reported a family in which four males had MR, microcephaly, hypogonadism, and short stature. Linkage studies were not conclusive but suggested localization in Xq25-q27.

• XLMR-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.

• XLMR-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.

• XLMR-symphalangism-hearing loss-immunodeficiency (Oosterwijk et al., Am J Hum Genet 65:A337, 1999). Based on three affected males with the above manifestations and other dysmorphism. The gene was localized to Xp11.4-q24.

• XLMR-spondyloepimetaphyseal dysplasia (Bieganski et al., Eur J Pediatr 158:809, 1999). Based on 3 male cousins with mild MR 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.

• XMRE. An X-linked mental retardation 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 STK9, and the XLMR-epilepsy syndrome localized to Xq22 with expression in females.

MRX Families, Loci and Genes

• MRX8: Mutation in DLG3

• MRX17: Duplication of Xp11.22 - RIBC1, HSD17B10, and HUWE1 (Froyen et al. Am J Hum Genet 82:432, 2008)

• MRX21: Mutation in IL1RAPL1 (Tabolacci et al., Am J Med Genet 140A:482, 2006)

• MRX31: Duplication of Xp11.22 - RIBC1, HSD17B10, and HUWE1 (Froyen et al. Am J Hum Genet 82:432, 2008)

• MRX34: Microdeletion of IL1RAPL1 (Raeymaekers et al., Am J Med Genet 64:16, 1996)

• MRX36: Mutation in ARX (Frints et al., Am J Med Genet 112:427, 2002)

• MRX43: Mutation in ARX (Bienvenu et al., Hum Mol Genet 11:981, 2002)

• MRX50: Xp11.4-p11.21

• MRX51: Xp11.4-p11.3

• MRX52: Xp11.21-q21.32

• MRX53: Xq22.2-q26

• MRX54: Mutation in ARX (Bienvenu et al., Hum Mol Genet 11:981, 2002)

• MRX55: Mutation in PQBP1 (Kalscheuer et al., Nat Genet 35:313, 2003)

• MRX56: Xp21.1-p11.21

• MRX57: Xq24-q25

• MRX58: Mutation in TM4SF2 (Zemni et al., Nat Genet 24:167, 2000)

• MRX59: Mutation in AP1S2 (Tarpey et al., Am J Hum Genet 79:1119, 2006)

• MRX60: mutation in OPHN-1 (Billuart et al., Nature 392:923, 1998)

• MRX61: Xq13.1-q25

• MRX62: Xq21.33-q25

• MRX63: Mutation in FACL4 (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: Mutation in 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)

• 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: Mutation in ARX (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: Mutation in MECP2 (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)

• 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)

• MRX87: ARX mutation (LaPeruta et al., BMC Med Genet 8:25, 2007)

• MRX88: AGTR2 mutation (Vervoort et al., Science 296:20401, 2002)

• MRX89: ZNF41 mutation (Shoichet et al., Am J Hum Genet 73:1341, 2003)

• MRX90: DLG3 mutation (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 mutation (Lugtenberg et al., Am J Hum Genet 78:215, 2006)

II. Genes Cloned

• AGTR2: The angiotensin II receptor type 2 has been implicated in XLMR with optic atrophy and nonsyndromal XLMR (Vervoort et al., Science 296:2401, 2002). The gene is located in Xq24. Mutations in a number of individuals and several XLMR 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 MR 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 MR, 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 XLMR 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 XLMR-hydrocephaly-basal ganglia calcifications (Fried syndrome). Borck et al. (Hum Mutat April 21, 2008-epub ahead of print) 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 XLMR 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 XLMR. The syndromal XLMR 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 MR 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 XLMR-epilepsy syndrome (XMRE), which maps to Xp11.4 (Ramser et al. Hum Mol Genet 14:1019, 2005).

• 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 MR, macrocephaly, prominent forehead and large cupped ears.

• CASK: Piluso et al. (13th Workshop on Fragile X and XLMR: 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).

• 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 XLMR, 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 XLMR. 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 XLMR 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 mental retardation, 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 XLMR (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 XLMR 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. GRIA3 had been previously identified as an MR candidate gene by Gecz et al. who reported a female with MR 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 XLMR 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 mental retardation, 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 had missense mutations of HUWE1.

• 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 MR (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. Abidi et al. (13th International Workshop on Fragile X and XLMR: Venice, 2007) has reported four mutations in patient with short stature and hyperreflexia.

• JARID1C: 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 MR (Santos et al., Eur J Hum Genet 14:583, 2006).

• 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 MR, 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 mental retardation, hypotonia, seizures, spastic quadriplegia, hydrocephalus, absence of language, gastrointestinal reflux, and abnormal movements. One of the inversion breakpoints interrupted KIAA2022 (Xp13.2). 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 XLMR.

• 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, mental retardation 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.

• MCT8 (SLC16A2): Friesema et al. (Lancet 364:1435, 2004) reported two deletions and three missense mutations in five unrelated males with severe mental retardation, 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) and Jansen et al. (J Clin Endocrinol Metab 92:2378, 2007) published additional AHDS families with MCT8 mutations. Wemeau et al. (J Clin Endocrinol Metab March 11, 2008-epub ahead of print) 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 XLMR. Orrico et al. (FEBS Letters 24106:1, 2000) found an A140V mutation in a family in which both males and females had MR. 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 XLMR family previously reported by Claes et al. (Clin Genet 52:155, 1997). The phenotype consisted of severe MR 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 XLMR 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 MR 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 70:1034-1037, 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 MR 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 MR 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 XLMR-hypotonia-recurrent infections, the family published by Pai et al. (J Med Genet 34:529, 1997) as a new XLMR 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) have reported other cases.

• 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.

• 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.

• 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 MR, 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 XLMR, epilepsy, and cerebellar hypoplasia (Bergmann et al., Brain 126:1537, 2003) and in 2 other XLMR families with cerebellar hypoplasia (Philip et al., J Med Genet 40:441, 2003). Functionally, the OPHN1 protein is required for dendritic spine morphogenesis (Govek et al., Nat Neurosicence 7:364, 2004).

• 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 2008, in press) have found mutations in the protocadherin 19 gene in seven families with epilepsy and mental retardation limited to females (EMRF). The gene is in Xq22. Scheffer et al. (Brain 2008, in press) reported the clinical findings separately. The absence of findings (epilepsy and MR) in males, they propose, is due to rescue by a protocadherin gene (PCDH11Y) on the Y chromosome.

• 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 XLMR-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 XLMR syndrome. Abidi et al. (Clin Genet 72:11, 2007) found a truncating mutation in one individual in a cohort of 26 with MR and cleft lip/palate.

• 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, Nat Genet 35:313, 2003). Different truncating mutations have been found in the original Renpenning syndrome family, in another XLMR 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 (MR, 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).

• 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 MR 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 XLMR family and a second mutation (c.19C→T, p.R7C) found in 4/290 black males with MR was reported by Srivastava et al. (12th International Fragile X/XLMR Workshop, Williamsburg, VA 2005). No clinical details were given in the abstract.

• SLC6A8: A nonsense mutation (R514X) in the creatine transporter gene located in Xq28 has been described in a seven year old boy with mild mental retardation 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 XLMR population. Clark et al. (Hum Genet 119:604, 2006) found a lower prevalence (1%) in males with MR 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 MR, 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 Schwartz and Friez (personal communications).

• 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 online, June 2008) reported a second mutation (missense in the N-terminal region) which causes severe mental retardation and seizures. Schwartz (personal communication) has found mutations in two additional families.

• SOX3: Laumonnier et al. (Am J Hum Genet 71:1450, 2002) have described mutations in SOX3 in the XLMR-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 mental retardation, 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 (CDKL5): 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 mental retardation 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 mental retardation, seizures and clinical findings overlapping those of Rett and Angelman syndromes.

• 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 MR and behavioral difficulties.

• TM4SF2: 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 MR 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 XLMR (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.

• 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.

• 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 XLMR by Tarpey et al. (Nat Genet 39:1127, 2007). The three truncating mutations produced syndromic phenotypes; the missense mutation produced nonsyndromal XLMR.

• XNP: Mutations in the gene responsible for XLMR-hypotonic facies (alpha-thalassemia mental retardation) 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. These findings confirm that a number of named XLMR 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 XNP which result in decreased expression have also been found to cause the XLMR-hypotonic facies phenotype (Thienpont et al., Eur J Hum Genet 15:1094, 2007).

• ZDHHC9: Raymond et al. reported frameshift, missense, and splice site mutations in the palmitoyltransferase gene (Xq26.4) in males with moderate MR, 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 mental retardation 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 XLMR linked to the region found one nonsense mutation and study of 306 other males with XLMR 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 mental retardation and an X:9 translocation. A missense mutation has been found in MRX45 (Kleefstra et al., J Med Genet 41:394, 2004).

Additional information may be obtained from Charles Schwartz (ceschwartz@ggc.org) or Roger Stevenson (res@ggc.org).

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