要旨
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.
