Mental Retardation, X-Linked, Syndromic, Claes-Jensen Type

A number sign (#) is used with this entry because of evidence that the Claes-Jensen type of X-linked syndromic mental retardation (MRXSCJ) is caused by mutation in the JARID1C gene (KDM5C; 314690) on chromosome Xp11.

Clinical Features

Claes et al. (2000) described a kindred in which 4 males in 2 generations in an X-linked recessive pedigree pattern had severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia.

Jensen et al. (2005) described 7 families with X-linked mental retardation (XLMR) and mutation in the JARID1C gene. In 3 of these families the mental retardation was syndromic. One family was that reported by Claes et al. (2000); Jensen et al. (2005) noted the additional features of aggressive behavior and strabismus. In another family, 2 brothers and their sister with severe mental retardation shared a conspicuous phenotype including spasticity, epileptic seizures, short stature, microcephaly, hypermetropia, and small feet. The third syndromic family included 4 affected males who presented with mental retardation and microcephaly. Of the 3 for whom clinical data were available, all had mildly dysmorphic facial features; additionally, 1 had small testes and another a small penis. All patients examined by Jensen et al. (2005) had a normal karyotype, and fragile X syndrome (300624) had been ruled out.

Santos et al. (2006) reported 2 brothers with X-linked mental retardation associated with a mutation in the JARID1C gene (314690.0005). Both had severe mental retardation with an overfriendly and anxious character. Other features included large ears with raised lobes, big hands with large fingers and proximal thumbs, prominent and separated superior incisors, scrotal tongue, and pectus excavatum. The unaffected mother was heterozygous for the mutation.

In 4 of 287 probands with X-linked mental retardation, Abidi et al. (2008) identified 4 different mutations in the JARID1C gene (see, e.g., 314690.0007). Clinical findings of 9 affected males from the 4 families included mental retardation in all, short stature in 5 (55%), hyperreflexia in 7 (78%), seizures in 3 (33%) and aggressive behavior in 4 (44%). The degree of mental retardation was mild in 2 males, moderate in 1, and severe in 5.

Santos-Reboucas et al. (2011) reported a Brazilian family with JARID1C/KDM5C-related X-linked mental retardation confirmed by genetic analysis (314690.0008). There were 3 affected brothers with severe mental retardation, poor speech, short stature, low weight, microcephaly, high palate, slight maxillary hypoplasia, and small feet. Their mother, who also carried the mutation, was mildly cognitively impaired.

Rujirabanjerd et al. (2010) reported a family in which 3 males had moderate mental retardation associated with microcephaly, large ears, and short stature. Genetic analysis identified a mutation in the KDM5C gene (P554T; 314690.0009). Two of 6 female carriers had learning difficulties. The family had previously been designated as MRX13 (Kerr et al., 1992).

Clinical Variability

Adegbola et al. (2008) reported a 4-year-old boy with cognitive impairment and features of autism. Detailed neuropsychologic testing of the patient showed significant delays in perception, fine motor skills, cognitive and language skills, and difficulty with self-regulation. He also showed impairments in social reciprocity and use of nonverbal behavior, stereotyped mannerisms, and adherence to routine, consistent with autistic spectrum disorder. Although he had no dysmorphic features as observed in many patients with JARID1C-related mental retardation, Adegbola et al. (2008) noted that the phenotype associated with mutations in the JARID1C gene is variable with regard to dysmorphism and cognitive impairment; the authors suggested that this patient falls within a milder end of the spectrum. Molecular analysis identified a hemizygous mutation in the JARIDIC gene (314690.0006), which was also identified in his unaffected mother.

Mapping

By means of multipoint linkage analysis with 24 highly polymorphic markers, Claes et al. (2000) excluded both the PLP1 (300401) and L1CAM gene (308840) in their affected kindred. Evidence suggested linkage to 2 regions: Xp21.1-q21.3 and Xq23-q27.1 (lod scores less than 3.0). Claes et al. (2000) suggested that this family represented a previously undescribed X-linked spastic paraplegia-mental retardation syndrome. Bohan and Azizi (2004) noted that the X-linked spastic paraplegia family reported by Claes et al. (2000) showed linkage to the same region as the Allan-Herndon-Dudley syndrome (AHDS; 300523) on Xq21, and suggested that the family may have had that disorder.

Molecular Genetics

In a systematic screen of brain-expressed genes from the proximal Xp and pericentromeric regions of the X chromosome in 210 families with X-linked mental retardation, Jensen et al. (2005) identified 7 different mutations in JARID1C (314690), including 1 frameshift and 2 nonsense mutations, as well as 4 missense mutations that altered evolutionarily conserved amino acids. In 2 of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families resulted from functional loss of the JARID1C protein. The authors estimated that the frequency of mutations in the JARID1C gene account for 2.8% to 3.3% of families with XLMR.