Mental Retardation, X-Linked 99, Syndromic, Female-Restricted

A number sign (#) is used with this entry because of evidence that female-restricted X-linked syndromic mental retardation-99 (MRXS99F) is caused by heterozygous mutation in the USP9X gene (300072) on chromosome Xp11.

Hemizygous mutation in the USP9X gene can also cause X-linked recessive MRX99 (300919), which is restricted to males.

Description

Female-restricted X-linked syndromic mental retardation-99 is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development and mild to moderate intellectual disability. Affected females can have a wide range of additional congenital anomalies, including scoliosis, postaxial polydactyly, mild cardiac or urogenital anomalies, dysmorphic facial features, and mild structural brain abnormalities (summary by Reijnders et al., 2016).

Clinical Features

Reijnders et al. (2016) reported 17 unrelated females, ranging in age from 2 to 23 years, with a complex syndromic neurodevelopmental disorder. All had delayed psychomotor development with mild to moderate intellectual disability and language delay. About half had hypotonia and some had early feeding and/or breathing difficulties as well as joint laxity. Congenital abnormalities were variable, but many were found in about 50% of patients: these included short stature, scoliosis, hip dysplasia, postaxial polydactyly, pes cavus, anal atresia, and hearing loss. Shared facial features included facial asymmetry, prominent forehead, bitemporal narrowing, short palpebral fissures, eye abnormalities, low or broad nasal bridge, prominent nose with flared nasal alae, thin upper lip, smooth long philtrum, dental abnormalities, and low-set posteriorly rotated ears. Eye abnormalities included cataracts, astigmatism, strabismus, myopia, and hypermetropia. Less common dysmorphic features included brachycephaly, up- or downslanting palpebral fissures, choanal atresia, pronounced nasolabial folds, small hands and feet, tapering fingers, and asymmetric hypomastia. Seven patients had mild cardiac defects, such as patent ductus arteriosus or atrial septal defect, and 5 had urogenital anomalies, including hydronephrosis or dysplastic kidneys. Other features included thyroid hormone abnormalities (in 6 patients), hypertrichosis (5 patients), sacral dimple (in 5 patients), seizures (in 4 patients), and recurrent respiratory tract infections. Two patients developed a malignancy. Common brain imaging abnormalities included hypoplastic corpus callosum, cerebellar hypoplasia, enlarged ventricles, and an abnormal gyral pattern in the frontal lobes. Five patients had a Dandy-Walker malformation. Eleven patients had skin pigmentary abnormalities following the lines of Blaschko, consistent with somatic mosaicism. One of the patients had been reported by Brett et al. (2014).

Molecular Genetics

In 17 unrelated females ranging in age from 2 to 23 years with MRXS99F, Reijnders et al. (2016) identified 17 different de novo heterozygous mutations in or deletions involving the USP9X gene (see, e.g., 300072.0004-300072.0008). Most of the mutations were found by whole-exome sequencing and confirmed by Sanger sequencing; 12 of the 13 point mutations resulted in truncated proteins. Immunoblot and RT-PCR analysis of patient fibroblasts and lymphoblasts showed that the loss-of-function alleles resulted in significantly reduced USP9X protein and transcript levels compared to control females, but these levels were similar to those of normal control males. X-chromosome inactivation (XCI) was found to be skewed greater than 90% in 3 of the 5 tested patients, but skewing was not related to disease severity. In addition, there was no correlation between skewing of XCI and expression of mRNA or protein levels in studies of patient cells. Reijnders et al. (2016) suggested that there may be tissue-specific expression of USP9X that may influence the phenotype. Despite localization of wildtype USP9X to cilia, patient fibroblasts did not show any differences in ciliogenesis, ciliary length, or ciliary trafficking compared to controls.