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 ... 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).
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, ... 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 truncation. 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.
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 ... 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.