NSDHL variants have been reported in the literature in association with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects, MIM: 308050, MONDO: 0010621) and CK syndrome (MIM: 300831, MONDO: 0010441), characterized by delayed psychomotor development, intellectual disability, seizures, microcephaly, and dysmorphic features. NSDHL loss-of-function (LoF) variants cause CHILD syndrome in females and are usually lethal in males, while NSDHL hypomorphic variants cause CK syndrome in males and female carriers are typically unaffected.
Thus far, neurodevelopmental disorders such as intellectual disability or seizures have not been reported in individuals with a diagnosis of CHILD syndrome (PMIDs: 26014843, 16088165, 25533639, 15689440, 16549711, 25093865, 21753784, 29341259) but have been observed in CK syndrome. For this reason, the ID/Autism Gene Curation Expert Panel has opted to evaluate this gene’s relationship to CK syndrome; evidence related to NSDHL and CHILD syndrome is not considered here.
Variants in NSDHL have thus far only been reported in 3 multigenerational families with the CK syndrome presentation; affected males share consistent features of intellectual disability, seizures, microcephaly, and dysmorphic facial features. Reported variants include a frameshift in the last exon resulting in stop loss and extension (PMID: 19377476), and an in-frame deletion of a single amino acid in the original CK family (PMID: 21129721), both shown to be hypomorphic alleles (PMID: 21129721); and a missense variant with no functional studies (PMID: 25900314). Supportive segregation data is available in all three families. This gene-disease association is also supported by experimental evidence. NSDHL encodes an enzyme in the cholesterol biosynthesis pathway and patient-derived lymphoblastoid cells have increased methyl sterol levels similar to those observed in CHILD syndrome (PMID: 21129721). Additional support is provided by a mouse model exhibiting abnormal cortical development (PMID: 21129721). In summary, there is moderate evidence supporting an association between NSDHL and X-linked CK syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 1/20/21 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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