Mental Retardation, X-Linked, Syndromic 14

A number sign (#) is used with this entry because X-linked syndromic mental retardation-14 (MRXS14) is caused by mutation in the UPF3B gene (300298), which is involved in nonsense-mediated decay of mRNA transcripts, on chromosome Xq24. Some patients have nonsyndromic mental retardation.

Clinical Features

Tarpey et al. (2007) reported 4 unrelated families with X-linked mental retardation. Although the phenotype was variable, common features included mild to severe mental retardation, autistic features, slender build, poor musculature, long, thin face, high-arched palate, high nasal bridge, and pectus deformities. Two families had been diagnosed as having Lujan-Fryns syndrome (309520) and 1 as having Opitz-Kaveggia syndrome (OKS; 305450). One of the families had been reported by Graham et al. (1998).

Xu et al. (2013) reported a large Chinese family in which 3 living males and 1 deceased male had nonsyndromic mild mental retardation. None of the affected individuals was known to have additional physical abnormalities. Carrier females were unaffected.

Inheritance

The transmission pattern of mental retardation in the families reported by Tarpey et al. (2007) and Xu et al. (2013) was consistent with X-linked recessive inheritance.

Molecular Genetics

In affected members of 4 unrelated families with X-linked syndromic mental retardation, Tarpey et al. (2007) identified hemizygous mutations in the UPF3B gene (300298.0001-300298.0004).

Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation. They identified 3 separate nonrecurring truncating mutations in UPF3B that segregated absolutely with the phenotype. In addition to the X-linked mental retardation, affected family members had elements of the Opitz-Kaveggia and Lujan-Fryns syndromes.

By exome sequencing of a Chinese family with nonsyndromic X-linked mental retardation, Xu et al. (2013) identified a hemizygous mutation in the UPF3B gene (R430X; 300298.0003). X-chromosome inactivation studies in 3 carrier mothers showed that only 18%, 17%, and 13% of lymphocytes, respectively, expressed the mutant allele. PCR analysis of patient cells showed decreased levels of mutant mRNA in the patients, suggesting that it undergoes nonsense-mediated mRNA decay. Patient cells showed higher expression of the GADD45B gene (604948), a component of the classical nonsense-mediated decay pathway compared to controls, suggesting that the UPF3B mutation caused dysregulation of this pathway.