A number sign (#) is used with this entry because of evidence that Raynaud-Claes syndrome (MRXSRC) is caused by mutation in the CLCN4 gene (302910) on chromosome Xp22.

Raynaud-Claes syndrome is an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development. Additional features include behavioral problems, psychiatric disorders, seizures (variable forms), progressive ataxia, brain abnormalities, and facial dysmorphisms. Some heterozygous females are unaffected, whereas others are affected with a severity spectrum similar to that seen in males (summary by Palmer et al. (2018)).

Raynaud et al. (1996) reported a French family (MRX15) in which 5 males spanning 2 generations had nonsyndromic X-linked mental retardation. There were 3 living patients, all adults. Features included congenital and subsequent hypotonia, delayed motor delay, and severe mental deficiency with poor or absent speech. The patients also were moderately slender and had scoliosis; 2 had strabismus. None had seizures. Brain imaging in 1 patient showed cortical atrophy, but brain imaging in another was normal. There were no affected females in the family. Palmer et al. (2018) restudied the MRX15 family (their Family C) reported by Raynaud et al. (1996) and noted that all affected males had severe to profound intellectual disability and variable behavioral difficulties including anxiety, perseverations, and hyperactivity. Two female heterozygotes were reported to be unaffected.

Claes et al. (1997) reported a family (MRX49) in which 5 males spanning 2 generations had nonspecific mental retardation. Intellectual disability ranged from mild to moderate, and several attended special schools. All had delayed early development and most had poor speech. Two obligate female carriers had mild mental retardation and/or behavioral problems. Palmer et al. (2018) provided updated clinical information on the MRX49 family (their Family A) reported by Claes et al. (1997). Affected males initially reported as having borderline to severe intellectual disability were reclassified as having a more severe degree of intellectual disability. The males exhibited a variety of behavioral difficulties, including aggressive outbursts and autistic features, and one individual had an absence seizure disorder. Delayed language development was notable. One obligate female carrier had mild intellectual disability, and another was reported to have normal intelligence but autistic behavior.

Veeramah et al. (2013) reported a 14-month-old boy with severe developmental delay who presented with epileptic encephalopathy. He developed refractory complex partial seizures with secondary generalization at age 4 months. Other features included microcephaly, delayed psychomotor development, hypotonia, and dystonia.

Hu et al. (2016) reported 13 males from 3 unrelated families (N70, AU27, and AU4) with intellectual disability. Some patients also had hypotonia, seizures, behavioral abnormalities, and spasticity. One family had 1 affected female. In 1 family, affected individuals were noted to have coarse facial features. Palmer et al. (2018) reported updated clinical information on these families. One 16-year-old affected male in their Family E (AU27) had hypotonia since infancy and complex partial seizures that responded to treatment with carbamazepine. He was not considered to be dysmorphic and was clumsy and easily fatigued. The 3 clinically assessed affected males in Family E had behavioral and psychiatric conditions ranging from depression to bipolar disorder. Four obligate carrier females were reported to have normal intelligence and no psychiatric conditions. Family F (AU4) in Palmer et al. (2018) is a large Anglo-Australian family with 7 affected males and 5 heterozygous females. All affected males had a seizure disorder, including 4 with an infantile-onset epileptic encephalopathy phenotype associated with seizure-related death and mild to severe intellectual disability. Three males were reported to have behavior problems, including aggressive outbursts and autistic-like restricted interests, and one was diagnosed with bipolar disorder. The oldest surviving male in this family had progressive disease. He lost speech and developed diplegia in his thirties, which evolved into quadriplegic severe spasticity and muscle wasting. MRI performed at age 66 showed significant cerebral and cerebellar atrophy with significant white matter loss. Three of the 5 female heterozygotes were asymptomatic. One (IV:4) had an adult-onset psychiatric condition and developed tardive dyskinesia secondary to antipsychotic medication. Another heterozygous female (IV:5) was severely affected, with infantile-onset epileptic encephalopathy resistant to treatment, severe intellectual disability, and progressive neurologic deterioration. A CT scan at age 42 demonstrated ventriculomegaly and prominent sulci. Chromosomal microarray analysis, whole-genome sequencing, and X-inactivation studies did not reveal alternative explanations for her diagnosis. One affected male in Family D (N70) was reported to have moderate intellectual disability and anxiety, but no neurologic signs or seizure disorders. No information was available on female members of the family.

Palmer et al. (2018) described 10 previously unreported families and reviewed 6 previously reported families with X-linked intellectual disability due to mutation in CLCN4, including 5 females with de novo variants. Among 29 hemizygous males, the intellectual disability was borderline in 1, mild in 7, moderate in 9, and severe/profound in 12. Fifteen of the 29 had a seizure disorder, which was intractable in 8. Behavioral or mental health disorders were reported in 19, and abnormal MRI findings (cortical atrophy, corpus callosum hypoplasia, or white matter hyperintensities) were reported in 64% of those tested. Progressive neurologic symptoms, including ataxia and/or lower limb spasticity, were noted in 4 males from 2 families. Common dysmorphic features in older males included a long face with straight nose and a prominent pointed chin that became more 'squared off' with age, and a relatively flat midface. Facial features were not considered characteristic in younger males. The phenotype in heterozygous females with inherited CLCN4 variants was variable, ranging from unaffected (16/18) to mild or severe intellectual disability (2/18). X-inactivation studies of the severely affected female were noninformative. Five heterozygous females with de novo mutations in CLCN4 had a more severe phenotype consistent with the phenotype in hemizygous males. One had borderline, 2 had moderate, and 2 had severe/profound intellectual disability. All 5 had impaired language development. Two girls had seizure disorders of varying severity, 2 had self-injurious behaviors, and 1 was assessed as emotionally reactive. X-inactivation studies were not performed in the females with de novo CLCN4 mutations.

The transmission pattern of mental retardation in the family (MRX15) reported by Raynaud et al. (1996) was consistent with X-linked recessive inheritance.

The transmission pattern of mental retardation in the family (MRX49) reported by Claes et al. (1997) was consistent with X-linked dominant inheritance, in that 2 obligate female carriers were mildly affected.

Claes et al. (1997) added 2 families to the growing list of nonspecific X-linked mental retardation (XLMR) families in which the disease locus has been mapped to a specific site on the X chromosome. In the first family, designated MRX49, 5 male patients in 2 generations showed mild to moderate mental retardation. By 2-point linkage analysis with 28 polymorphic markers, dispersed over the X chromosome, a maximum lod score of 2.107 was found with markers DXS7107 and DXS8051 at theta = 0.0, localizing the MRX49 locus at Xp22.3-p22.2. Multipoint linkage analysis showed negative lod scores over all regions of the X chromosome. The second family was designated MRX50 (300115). Claes et al. (1997) reviewed other nonspecific XLMR families that had been mapped to the same region as MRX49 (e.g., MRX19, MRX24, and MRX37) and suggested that these may be allelic disorders.

The location of a nonspecific X-linked mental retardation locus (MRX49) in the Xp22.3 region was supported by the finding of Spranger et al. (1999) of a contiguous gene syndrome that included clinical features referable also to involvement of the SHOX gene (312865) and the ARSE gene (300180), which mapped to that region.

In a 14-month-old boy with severe developmental delay who presented with epileptic encephalopathy, Veeramah et al. (2013) identified a de novo hemizygous missense mutation in the CLCN4 gene (G544R; 302910.0001). The mutation was found by whole-exome sequencing. In vitro functional expression studies in Xenopus oocytes showed that the mutation almost abolished the outwardly rectifying currents, consistent with a loss of function. The patient was 1 of 10 probands with a similar phenotype who underwent whole-exome sequencing.

In affected male members of 5 unrelated families with X-linked intellectual disability, including the MRX49 family reported by Claes et al. (1997) and the MRX15 family reported by Raynaud et al. (1996), Hu et al. (2016) identified hemizygous mutations in the CLCN4 gene (302910.0002-302910.0006). The mutations were found by X-chromosome exome sequencing. One of the mutations resulted in a truncated protein, whereas the 4 others were missense mutations. In vitro functional expression studies in Xenopus oocytes showed that all of the missense mutations caused a marked reduction in outwardly-rectifying CLCN4 currents compared to wildtype. Knockdown of the Clcn4 gene in mouse hippocampal neurons resulted in 30% less dendritic branches compared to controls, and primary neurons derived from Clcn4-null mice showed similar, but more subtle, changes. The findings were consistent with a loss of function underlying the cognitive defects in these families.

Palmer et al. (2018) summarized phenotypic and molecular genetic information on 52 individuals from 16 families with a syndromic intellectual disability disorder, including 6 previously reported families, and mutation in the CLCN4 gene. In 5 affected females (see, e.g., 302910.0007) and 2 affected males, the mutations occurred de novo. The mutation spectrum included frameshift, missense, and splice site variants, and one single-exon deletion.

The Human Gene Mapping Nomenclature Committee (Mulley et al., 1992) proposed to designate each newly reported apparently unique X-linked mental retardation (MRX) family with gene symbols (e.g., MRX1, MRX2) if a minimal lod score of 2.0 was demonstrated between the MR locus and one or more X chromosome markers.