XLID

Information posted on this page is intended to complement and update the Atlas of X-Linked Intellectual Disability Syndromes, Edition 2, by R.E. Stevenson, C.E. Schwartz, and R.C. Rogers (Oxford University Press, 2012).

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
  2. New Gene Identification
  3. MRX Families, Loci and Genes
  4. Segmental X Chromosome Duplications
  5. Figures (4) and Table of Gene Identifications

I.   New Syndromes and Localizations

  • Criado (An Pediatr (Barc) 76:184, 2012) described eight males in one family with ID, short stature, microcephaly, hypertelorism, genital hypoplasia and variable skeletal findings. The gene locus mapped to Xp11.23-q21.32 (LOD 2).
  • 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 earlobes and short stature. The entity was mapped to a 16cM region in Xq24 (maximum lod score 3.61 at DSX1001). This entity looks like the condition XLID-hypogonadism-tremor (Cabezas syndrome) which results from mutations in CUL4B.
  • XLID-Retinoschisis. Phadke et al. (Am J Med Genet 155:9, 2011) reported 2 brothers with ID, short stature, microcephaly, and retinoschisis. Sequencing of RS1 and microarray covering Xp22.1 was normal. The boys were concordant for 4 different regions – Xp22.33-p22.2, Xp11.3-p21.31, Xq23-q25 and Xq27.1-q28.
  • X-linked Cornelia de Lange syndrome. Mutations in two genes, SMC1A (SMC1L1) in Xp11.2 and HDAC8 in Xq13 have been implicated in X-linked Cornelia de Lange syndrome (Deardorff et al.: Am J Hum Genet 80:485, 2007 and 2011 David W. Smith Workshop on Malformations and Morphogenesis, Lake Arrowhead, CA, Sept. 9-12, 2011). An intronic variant in HDAC8 was described in a large family with XLID, hypogonadism, short stature and facial dysmorphisms different from Cornelia de Lange syndrome by Harakalova et al.: J Med Genet 49:539, 2012.
  • X-linked Kabuki syndrome. Miyake et al. (Hum Mut 34:108, 2013) reported identified 3 mutations (2 nonsense, 1 inframe deletion) in KDM6A in patients with Kabuki syndrome who did not have mutations in MLL2. The gene is located in Xp11.3 and encodes a lysine demethylase. Lederer et al. (AJHG 90:119, 2012) had previously reported deletion of the gene in three patients with Kabuki syndrome.

II.   New Gene Identification

  • AIFM1. Using exome sequencing, Rinaldi et al. (Am J Hum Genet 91:1095, 2012) found a missense mutation in AIFM1 in the family originally reported with Cowchock variant of Charcot-Marie-Tooth syndrome (CMTX4).
  • BCAP31. Cacciagli et al. (Am J Hum Genet 93:579, 2013) reported a mutation in BCAP31 in 3 families with XLID, microcephaly, short stature, strabismus, optic atrophy, deafeness, dystonia, pyramidal signs, quadriplegia, seizures and white matter hypomyelination. The gene located in Xq28 encodes a chaperone protein involved in endoplasmic reticulum functions and programmed cell death.
  • CCDC22 (Mol Psych 17:4, 2012). Voineagu et al. reported a missense mutation (p.T17A) that segregated with ID, cardiac anomalies, hip dislocation, scoliosis, hypoplastic distal phalanges, syndactyly, and facial abnormalities (hypertelorism, beaked nose with wide nasal tip, ear anomalies and high arched palate) in a large family with 6 affected males in 3 generations. The gene encodes a coiled-coil domain protein of unknown function.
  • CLIC2. Takano et al. (Hum Mol Genet 21:4497, 2012) found a missense mutation (p.H101Q) in CLIC2 in two brothers with profound ID, atrial fibrillation, cardiomegaly, congestive heart failure and seizures. Both had contractures of the large joints. Distinctive facial findings were not present. The mother was considered to be learning disabled. The gene is located in Xq28 and modulates the action of the ryanodine receptor intracellular Ca2+ release channels.
  • CNKSR2. Houge et al. (Mol Syndromol 2:60, 2011) reported a 234 kb deletion of Xp22.12, which removed the first 15 exons of CNKSR2 in a five-year-old boy with ID, microcephaly and seizures. The gene encodes the connector enhancer of KSR-2, is highly expressed brain and localizes to the postsynaptic density. The protein may have a role in MAPK signaling. The mutation appeared de novo in the mother who was normal.
  • EBP. Hartill et al. (J Med Genet Suppl 1 49:SP05, 2012) reported a missense mutation in EBP (p.W47R) in a kindred with 4 affected males in three generations. Affected males had aggressive behavior, toe 2-3 syndactyly and "soft dysmorphic signs." The gene, located at Xp11.23, encodes an enzyme (3-beta-hydroxysteroid-delta 8, delta 7-isomerase) involved in cholesterol metabolism and is known to be the cause of X-linked dominant chondrodysplasia punctata. This family had no signs of chondrodysplasia punctata.
  • IQSEC2. Mau-Them et al. (EJHG Epub May 15, 2013) reported 3 unrelated males with postnatal onset microcephaly, midline stereotypic hand movements, hypotonia, hyperactivity, strabismus and seizures with mutations (2 intragenic dups, 1 nonsense) in IQSEC2. Prior cases with mutations in IQSEC2 have been considered to be nonsyndromal (Nat Genet. 42:486, 2010; AJMG 30:485, 1988).
  • KDM6A. Lindgren et al. (Hum Genet 132:537, 2013) reported a female with an X:5 translocation which disrupted KDM6A, a histone 3 lysine 27 demethylase and histone 3 lysine 4 methyltransferase gene. The 19-year-old had global developmental delay, microcephaly, short stature, large posteriorly-rated ears, downslanted palpebral fissures, arched eyebrows, myopia, short columella, short philtrum, cleft palate, abnormally-shaped dysplastic teeth, pectus excavatum, clinodactyly, short metacarpals and metatarsals, puffy fingers, hyperconvex nails, ventriculomegaly, hypotonia and seizures. The authors found reports of 7 duplications and 2 deletions of KDM6A in other individuals with some phenotypic overlap. They also noted that individuals with Kabuki syndrome have similar clinical findings and some have had deletions or point mutations in KDM6A.
  • PIGA. Three reports since 2012 have implicated PIGA at Xp22 as an XLID gene. Johnston et al. (AJHG 90:295, 2012) reported 3 males in one family with an infancy lethal disorder characterized by central hypotonia, seizures, small nose with depressed nasal bridge, upslanting palpebral fissures, gingival overgrowth, short neck, small nails, short digits, hyperreflexia, thin corpus callosum and small cerebellum. Swoboda et al. (AJMG 164A:17, 2013) reported 3 related males with neurological degeneration, systemic iron storage, brown skin papules and scattered areas of hyperpigmentation with an inframe deletion in PIGA. They suggested the name Ferro-Cerebro-Cutaneous syndrome. Affected males also showed acquired microcephaly, alveolar ridge overgrowth, seizures, muscle atrophy, spasticity, contractures, hepatomegaly and splenomegaly. Van der Crabben et al. (AJMG 164A:29, 2013) reported a missense mutation in this phosphatidyl inositol glycan class A gene in a boy with severe developmental delay and regression, central hypotonia, seizures, high frontal hairline, long philtrum, alveolar overgrowth, unerrupted teeth, accelerated statural growth, deep plantar creases, thin corpus callosum, cerebral atrophy and elevated alkaline phosphatase. Maternal X-inactivation was markedly skewed.
  • SSR4. Losfeld et al. (Hum Mol Genet Nov. 13, 2013) reported a de novo single base deletion in SSR4, a gene in Xq28 which encodes a protein in the heterotetrameric translocon-associated protein complex in a 16 year old teenager with microcephaly, ID, seizures and gastroesophageal reflux. The protein is involved in N-glycosylation, hence represents a new congenital disorder of glycosylation.
  • SYP. Tarpey et al. (Nat Genet 41:535, 2009) reported 4 mutations, three of them truncating, in SYP which encodes an integral membrane protein of small synaptic vesicles. The ID was mild to moderate. Some affected males had seizures, but other findings were inconsistent.
  • TMLHE. Alterations in this gene located adjacent to PAR2 in Xq28 has been implicated as a risk factor for autism. Some of the affected males also have ID, others have normal intelligence. The gene encodes 6-N-trimethyllysine dioxygenase, the first enzyme in carnitine synthesis. A deletion of exon 2 is the most common alteration and is found 2.8 fold more frequently in male siblings with autism than in sporadic autism or in controls (Celestino-Soper et al. PNAS USA 109:7974, 2012). Nonsense and missense mutations have also been reported (Nava et al. Transl Psychiatry 2:e179, 2012).
  • WDR45. Saitsu et al. (Nat Genet 45:445, 2013) reported 5 females with globally delayed development in childhood and neurodegeneration with seizures, dystonia, rigidity, tremors, brain iron accumulation and cerebral atrophy in early adulthood. The gene, located at Xp11.23, may have diverse cellular functions including autophagy. Prior reports of this distinctive form of neurodegeneration with brain iron accumulation include those of Gregory et al. (J Med Genet 46:73, 2009) and Haack et al. (AJHG 91:1144, 2012).
  • ZC4H2. Hirata et al. (AJHG 92:1, 2013) reported mutation in the zinc-finger gene ZC4H2 in four families with arthrogryposis and 1 family with cerebral palsy. Carrier females were affected but to a lesser degree. The gene is located in Xq11.2. Miles-Carpenter syndrome (AJMG 38:215, 1991) also harbors a mutation in this gene (CE Schwartz, unpublished).
  • ZNF711. Tarpey et al. (Nat Genet 41:535, 2009) reported truncating mutations in ZNF711 in 2 families. Both families were said to have moderate ID without other distinctive findings.

III.  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
  • ATRX (XNP)
  • SCL16A2 (MCT8)
  • AFF2 (FMR2)
  • SLC6A8

IV.  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. Flynn et al. (Am J Med Genet 155A:141, 2011) reported a 4.7 Mb duplication of this region in a male with cerebral atrophy but normal head circumference, moderate cognitive impairment, short stature, small testes, seizures and adult-onset regression. They considered his facial features to resemble Renpenning syndrome.
  • 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. Honda et al. (J Hum Genet 55:590, 2010) reported three additional families.

V. Summary of XLID Maps and Genes - Updated February 2014

The linkage limits for XLID syndromes and non-syndromal XLID and the band locations for cloned XLID genes are provided in the accompanying illustrations. Click to download figures as PowerPoint slides. A Table is also available (PDF) showing the genes involved in X-linked intellectual disability in order of their discovery.

  • Figure 1 - Location of the genes for XLID syndromes which have been cloned and mutations demonstrated.
  • Figure 2 - Linkage limits for XLID syndromes which have been mapped (lod score >2), but the genes not yet cloned.
  • Figure 3 - Linkage limits for MRX families which have been mapped (lod score >2), but the genes not yet cloned. The locations of the MRX genes which have been cloned are indicated on the left with solid arrows, genes that cause MRX and MRXS are shown on the right with open arrows.
  • Figure 4 - Location of Segmental Duplications Associated with XLID
  • Table - Listing of XLID genes and gene functions chronologically by year of discovery.