Mental Retardation, X-Linked 21

A number sign (#) is used with this entry because X-linked mental retardation-21 (MRX21) is caused by mutation in the IL1RAPL1 gene (300206) on chromosome Xp21.

Description

This form of nonsyndromic X-linked mental retardation is characterized by a spectrum of cognitive neurologic impairments or disabilities ranging from moderate mental retardation to high-functioning autism. Males are typically severely affected, but some carrier females may manifest milder deficits (summary by Piton et al., 2008).

Clinical Features

Kozak et al. (1993) reported a 3-generation Italian family in which 4 male patients had moderate mental retardation without any specific or consistent phenotypic abnormalities. One obligate female carrier had mild retardation and another 2 had normal intelligence, suggesting incomplete penetrance in females.

Piton et al. (2008) reported a family in which 3 brothers had mental retardation with variable autistic features. The 8-year-old proband had mental retardation and showed some autistic signs, but was too impaired to be formally tested. The proband's 2 brothers had a less severe cognitive phenotype: one had pervasive developmental disorder, not otherwise specified (PDDNOS), and the other had mild mental retardation with repetitive behaviors, but no other signs of autism. Their carrier mother was unaffected.

Franek et al. (2011) reported 2 unrelated families with X-linked mental retardation resulting from deletions encompassing the immunoglobulin domain of the IL1RAPL1 gene. Three affected males in the first family had low IQ and other variable features, including hypotonia (2), pectus excavatum (2), prominent jaw (2), synophrys (2), and hyperextensible joints (2). Two had behavioral abnormalities, including impulsivity, oppositional disorder, and hyperactivity. One had pigmentary skin changes. Genetic analysis identified a 635-kb deletion spanning exons 2-5 in the IL1RAPL1 gene (see 300206.0003), although exact deletion breakpoints were not mapped. In the second family, there were 5 affected males, but only 2 brothers were described in detail. Both had moderate intellectual disability and seizures. Both had prominent jaw, strabismus, and hyperextensible elbows; 1 had synophrys and the other had depression. One of the brothers carried a fragile site at Xq28 (FRAXF; 300031) (Parrish et al., 1994), and both had a deletion of exons 1-5 of the IL1RAPL1 gene, which was inherited from their unaffected mother. None of the patients reported by Franek et al. (2011) had autism.

Clinical Variability

Piton et al. (2008) reported a French Canadian girl with high functioning autism consistent with Asperger syndrome and no mental retardation who had a heterozygous de novo 7-bp deletion (1730delTACTCTT) in exon 9 of the IL1RAPL1 gene, resulting in a frameshift and premature termination. The truncated protein was predicted to lack part of the transmembrane domain as well as the entire cytoplasmic domain and was not found in 276 control chromosomes. Although in vitro studies in rat hippocampal cells indicated that the deletion resulted in a loss of function, transfection of the truncated mutant alone did not affect neurite outgrowth.

Mapping

By linkage analysis of a 3-generation Italian family with X-linked mental retardation, Kozak et al. (1993) found linkage to Xp22.3-p21.1 (maximum lod = 2.11 at theta = 0.00 with markers DXS164 and DXS278).

Cytogenetics

Fries et al. (1993) reported mentally retarded female carriers in 2 Xp21 deletion syndrome families with Duchenne muscular dystrophy (DMD; 310200), glycerol kinase deficiency (GKD; 307030), and adrenal hypoplasia (AHC; 300200) in affected males. In the first family, with normal karyotypes, a submicroscopic deletion was associated with DMD in the retarded male and with retardation in carrier females. In the second family, an X chromosome with a cytogenetically deleted Xp21 distal to the OTC (300461) and RP (see 312610) genes segregated in the affected male and retarded female carriers.

Raeymaekers et al. (1996) described a Belgian family with 6 males with nonspecific moderate mental retardation associated with a microdeletion in the Xp22.1-p21.3 region. The family was designated MRX34. There was allelic loss of DXS1218 in all affected relatives.

Billuart et al. (1996) carried out PCR screening of DNA samples from 192 patients with MRX for the presence of deletions in the Xp22.1-p21.3 region in which a nonspecific mental retardation locus had been assigned on the basis of deletions associated with contiguous gene syndromes (Fries et al., 1993), linkage analysis (Kozak et al., 1993), and other evidence. Billuart et al. (1996) analyzed a panel of 12 X-linked microsatellites that map between POLA (312040) and DXS1020 on chromosome Xp22.1-p21.3. Analysis of 192 mentally retarded males led to the identification of a microdeletion that extended from DXS1202 to DXS1065 in 1 case of nonspecific X-linked severe mental retardation. The presence of the deletion was confirmed by Southern blot analysis using a probe at the DXS28 locus that maps between the microsatellite markers DXS1202 and DXS1065.

Des Portes et al. (1998) reported a family in which 2 males had nonspecific moderate mental retardation with no additional neurologic impairment, statural growth deficiency, or dysmorphic features. Both boys had a microdeletion in Xp22.1-21.3, which included markers DXS1202, DXS1061, and DXS1218. The authors cited 9 unrelated families affected with nonspecific mental retardation assigned to Xp22.1-p21.3.

In a 6-year-old boy with mental retardation, Lepretre et al. (2003) identified an X chromosome inversion, inv(X)(p21.3q27.1). A similar chromosomal rearrangement was detected in his mildly mentally retarded mother. FISH, using a panel of ordered YAC clones, allowed the identification of YACs spanning both the Xp21.3 and Xq27.1 breakpoints, where many nonspecific mental retardation loci had been reported. Further investigations by FISH showed that the IL1RAPL1 gene at Xp21.3 was disrupted by the inversion.

Bhat et al. (2008) reported a 7-year-old boy with developmental delay, features of autism, facial dysmorphism, and a pericentromeric inversion disrupting the IL1RAPL1 gene: inv(X)(p22.1q13). His mother, who also carried the inversion, had mild mental retardation and autism. She had also experienced a severe CNS infection as an infant.

Molecular Genetics

In a small family with X-linked mental retardation, Carrie et al. (1999) identified a mutation in the IL1RAPL1 gene (300206.0001). The results suggested that signal transduction through multifunctional proteins of the immune system may be critical for the development of physiologic processes underlying cognitive function.

In 4 affected males from a family originally reported by Kozak et al. (1993) and designated MRX21, Tabolacci et al. (2006) identified a mutation in the IL1RAPL1 gene (300206.0002). Two female mutation carriers demonstrated learning disabilities, although blood leukocytes showed X-inactivation patterns favoring the wildtype allele. Tabolacci et al. (2006) suggested that brain neurons may show different X-inactivation patterns.

In 4 affected males in a family segregating nonspecific mental retardation showing linkage to Xp22.11-p21.2, Nawara et al. (2008) identified a deletion of exons 2, 3, 4, and 5 in the IL1RAPL1 gene (300206.0003). The deletion was also identified in 3 obligatory female carriers, who were apparently of normal intelligence.

In 3 brothers with variable severity of cognitive impairment, ranging from mental retardation to autistic features, Piton et al. (2008) identified a hemizygous 730-kb deletion in the IL1RAPL1 gene (300206.0004). The mother carried the deletion but did not show any cognitive or behavioral abnormality. The deletion was identified by whole-genome search of copy number variants using comparative genomic hybridization.

Franek et al. (2011) identified a 635-kb deletion spanning exons 2-5 in the IL1RAPL1 gene (see 300206.0003) in 3 males from a family with X-linked mental retardation, although exact deletion breakpoints were not mapped. Two affected males from a second family had a deletion of exons 1-5 of the IL1RAPL1 gene, which was inherited from their unaffected mother. Franek et al. (2011) concluded that loss of function of the IL1RAPL1 protein is associated with intellectual disability.