Mental Retardation, X-Linked 98

A number sign (#) is used with this entry because X-linked mental retardation-98 (MRX98) is caused by hemizygous or heterozygous mutation in the KIAA2022 gene (NEXMIF; 300524) on chromosome Xq13.

Description

X-linked mental retardation-98 is a neurodevelopmental disorder characterized by delayed psychomotor development, poor speech, behavioral abnormalities, poor overall growth, dysmorphic facial features, and often early-onset seizures. Some carrier females are unaffected, whereas other females with mutations are affected; males tend to be more severely affected than females. It is believed that the phenotypic variability and disease manifestations in female carriers results from skewed X-inactivation or cellular mosaicism (summary by de Lange et al., 2016).

Clinical Features

Van Maldergem et al. (2013) reported 9 affected males from 4 unrelated families with nonsyndromic X-linked mental retardation. One of the families with 2 affected individuals had previously been reported by Cantagrel et al. (2004). The patients had delayed psychomotor development, absent or poor speech development, and postnatal growth retardation, often with microcephaly. Some patients showed autistic behavioral features, such as stereotypic hand movements and repetitive behaviors. All of the patients had strabismus. Additional, more variable features included spasticity, axial hypotonia, seizures, drooling, gastroesophageal reflux, and lack of sphincter control. Some patients had dysmorphic features, including round face, short nose, short philtrum, and esotropia, although a specific pattern was not present. Female carriers were unaffected.

Kuroda et al. (2015) reported 2 unrelated Japanese boys with MRX98. Neither had a family history of the disorder, consistent with sporadic occurrence. Both had severely delayed psychomotor development apparent since early infancy, hypotonia, absent language, autistic features, and poor overall growth; 1 had microcephaly (-2.9 SD). The patients showed dysmorphic features, including upswept hair, narrow forehead, downslanting eyebrows, long nose, hypoplastic alae nasi, thin lips, open mouth, and large ears. One patient was described as having tic behavior with repetitive hand-flapping movement and tongue protrusion. The other boy developed nephrotic syndrome and central hypothyroidism, which may have been coincidental. Neither patient had seizures.

Affected Female Carriers

Farach and Northrup (2016) reported a 17-year-old girl with severe intellectual disability, speech limited to a few words, and refractory seizures since about 1 year of age. EEG showed multifocal and generalized epilepsy with multiple abnormal discharges. At age 17, she underwent a corpus callosotomy, which resulted in improved seizure frequency. She had short stature with poor overall growth and dysmorphic features, including thick coarse hair, bitemporal narrowing, prominent nasal bridge, brachydactyly, a single transverse palmar crease, and fifth finger clinodactyly. She was not toilet trained and had repetitive behaviors, aggression, and hyperactivity. Farach and Northrup (2016) noted the phenotypic similarities to males with MRX98.

De Lange et al. (2016) reported 14 female patients with de novo heterozygous mutations in the KIAA2022 gene. The patients were ascertained for study due to developmental delay or seizures. Thirteen patients had no family history of a similar disorder and had mild to severe intellectual disability. The fourteenth patient was diagnosed after her 2 sons with intellectual disability were found to carry a KIAA2022 mutation; she had a history of seizures but no intellectual disability. Two of the patients were also reported by Webster et al. (2017). Twelve of 14 patients reported by de Lange et al. (2016) had intractable epilepsy with myoclonic and/or absence seizures; 11 developed generalized seizures, and 5 had status epilepticus. EEG abnormalities included polyspike waves, spike waves, focal discharges, and background slowing. Most patients had refractory seizures despite being treated with antiepileptic medication. Six patients were noted to have developmental delay before the onset of seizures in infancy, and most had delayed walking with poor speech. Ten patients had behavioral abnormalities, including autism, aggression, and hyperactivity. More variable features included hypotonia, neonatal feeding difficulties, microcephaly, and mild nonspecific dysmorphic facial features.

Webster et al. (2017) reported 5 unrelated girls with severe global developmental delay, poor or absent speech, and early-onset intractable seizures. Additional features included hypotonia, ataxic gait, autism, attention-deficit disorder, hyperactivity, and gastroesophageal reflux or constipation.

Inheritance

The transmission pattern of MRX98 in the families reported by Van Maldergem et al. (2013) was consistent with X-linked recessive inheritance.

Cytogenetics

In 2 related males with severe mental retardation, Cantagrel et al. (2004) identified a pericentric inversion inv(X)(q13;p22) interrupting the KIAA2022 and P2RY8 genes (300525). RT-PCR showed that the KIAA2022 transcript was not expressed in the patients' cells, whereas the P2RY8 transcript was expressed; the amount of P2RY8 was similar in the cells of the affected patients and a tested carrier female. Because haploinsufficiency of the P2RY8 gene in carrier mothers did not have a phenotypic consequence, Cantagrel et al. (2004) concluded that the severe mental retardation of the affected males was due to the absence of the KIAA2022 gene product. However, screening of 20 probands from X-linked mental retardation families revealed no mutation in the KIAA2022 gene.

Molecular Genetics

In affected males from 3 unrelated families with X-linked mental retardation, Van Maldergem et al. (2013) identified 3 mutations in the KIAA2022 gene. Two of the mutations resulted in premature termination and loss of function (300524.0001 and 300524.0003), and the third was a duplication involving exon 1 (300524.0002) that resulted in a 60% decrease in KIAA2022 expression. The mutations were found by X-chromosome exome sequencing or microarray CGH analysis and segregated with the phenotype in the families. Carrier females were unaffected. Knockdown of KIAA2022 in cultured rat hippocampal neurons resulted in marked impairment in neurite outgrowth, including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function. The findings indicated that loss of KIAA2022 function can cause intellectual disability with autistic features. Kuroda et al. (2015) suggested that the microduplication identified in 1 of the families reported by Van Maldergem et al. (2013) was hypomorphic and that the patients had mild features; this may represent a correlation between genotype and disease severity.

In 2 unrelated Japanese boys with MRX98, Kuroda et al. (2015) identified de novo hemizygous truncating mutations in the KIAA2022 gene (Q705X and R322X; 300524.0004). The mutations were found by targeted sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a cohort of 13 Japanese males with intellectual disability who underwent targeted sequencing.

In a 17-year-old girl with MRX98, Farach and Northrup (2016) identified a de novo heterozygous R322X mutation in the KIAA2022 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies showed a random pattern (73:27). Farach and Northrup (2016) offered several possible reasons for why this female patient manifested disease with a heterozygous mutation, including specific location of the mutation, expression in a female, possible threshold effect of the inactivation results, and tissue-specific expression of the mutation.

In 14 females with MRX98, de Lange et al. (2016) identified de novo heterozygous truncating mutations in the KIAA2022 gene (see, e.g., 300524.0004-300524.0008). All mutations were predicted to result in a loss of function. X-inactivation studies were performed in 7 patients: 6 had random X inactivation, whereas 1 (patient 6) showed 100% skewing and complete absence of RNA expression in blood. The phenotype of patient 6 resembled that observed in males with KIAA2022 mutations. These findings suggested that the degree of KIAA2022 loss correlates with the severity of the disorder, with complete loss of expression predicting a more severe phenotype. De Lange et al. (2016) suggested that the clinical variability of MRX98 in females may be due to several factors, including X inactivation and cellular mosaicism.

In 5 unrelated girls with MRX98, Webster et al. (2017) identified de novo truncating mutations in the KIAA2022 gene. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. The authors suggested that skewed X inactivation with differential expression in the brain could explain why some female carriers are affected while others are asymptomatic carriers.