CLCN4-Related Neurodevelopmental Disorder

Excerpt

Clinical characteristics: CLCN4-related neurodevelopmental disorder (CLCN4-NDD), an X-linked disorder, is characterized in the 36 males reported to date by developmental delay or intellectual disability, behavioral/mental health issues (e.g., autism spectrum disorder, anxiety, hyperactivity, and bipolar disorder), epilepsy, and gastrointestinal dysfunction. The five heterozygous females with a de novo CLCN4 variant reported to date had findings very similar to those of affected males. Twenty-two of 25 heterozygous females identified in family studies following identification of an affected male were unaffected or had only mild specific learning difficulties and/or mental health concerns, whereas three were more severely affected.

Diagnosis/testing: The diagnosis of CLCN4-NDD is established in a male proband with suggestive findings and a hemizygous pathogenic variant in CLCN4 identified by molecular genetic testing. The diagnosis of CLCN4-NDD is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in CLCN4 identified by molecular genetic testing; however, the phenotype in females with a pathogenic variant can range from asymptomatic to severe.

Management: Treatment of manifestations: Treatment is supportive and often includes multidisciplinary specialists in neurology, pediatrics, mental health, physiatry, occupational and physical therapy, gastroenterology, feeding therapy, ophthalmology, audiology, and medical genetics.

Surveillance: Routine monitoring of neurologic findings (response to anti-seizure medications; emergence of new findings), development and educational progress, psychiatric/behavioral issues (response to medications; emergence of new findings), mobility and self-help skills, growth and gastrointestinal manifestations, ophthalmologic findings, hearing, and family support systems.

Genetic counseling: CLCN4-NDD is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the CLCN4 pathogenic variant. If the mother of a proband has a CLCN4 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may be unaffected or have clinical findings ranging from mild learning difficulties and mental health concerns to severe manifestations. If the proband represents a simplex case and if the CLCN4 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population. Once the CLCN4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.