NSDHL – CK syndrome

NSDHL encodes the 3β-hydroxysterol dehydrogenase involved in a late step of cholesterol biosynthesis. CK syndrome (CKS) is an X-linked recessive intellectual disability disorder affecting males with severe cognitive impairment, spasticity, seizures, microcephaly, plagiocephaly, and skeletal anomalies. Carrier females are typically asymptomatic obligate carriers. To date, thirteen male patients with CKS from two families and five additional affected males in a five-generation Lithuanian pedigree have been reported, expanding the cohort to ≥18 patients (PMID:21129721; PMID:25900314). This pattern supports X-linked recessive inheritance with complete penetrance in hemizygous males.

Genetic evidence for NSDHL in CK syndrome includes multiple unrelated pedigrees demonstrating segregation of hemizygous variants in affected males. In the initial kindreds, a 3 bp deletion c.696_698del (p.Lys232del) and a frameshift c.1098dup (p.Arg367SerfsTer33) co-segregated with disease in two families (PMID:21129721). Targeted sequencing in a Lithuanian family identified the missense mutation p.Gly152Asp in five males across five generations, confirming obligate carrier status in females (PMID:25900314). Additional alleles include canonical splice-site c.267+2T>C and missense c.457G>A (p.Val153Ile). All variants are absent from population databases and align with an X-linked recessive model.

The variant spectrum comprises missense substitutions, in-frame deletions, splice-site mutations, and frameshifts. In-frame deletions such as c.696_698del (p.Lys232del) recur in founder lineages, whereas c.1098dup (p.Arg367SerfsTer33) results in premature truncation. Missense variants c.457G>A (p.Val153Ile) and p.Gly152Asp reside in conserved domains. Splice-site disruptions like c.267+2T>C abolish canonical splicing. This allelic heterogeneity correlates with phenotypic variability in cognitive and motor manifestations.

Functional studies have consistently demonstrated that CK-associated NSDHL alleles are hypomorphic. Temperature-sensitive variants including c.696_698del (p.Lys232del) and p.Val153Ile display reduced stability at 37 °C with partial restoration at 30 °C, and complement Erg26-deficient yeast growth (PMID:21129721). Sterol profiling of patient-derived cells and CSF shows accumulation of methyl sterol intermediates despite normal cholesterol levels, implicating toxic sterol buildup (PMID:21129721). Complementation assays and chemical chaperone rescue with glycerol further restore mutant NSDHL expression, underscoring protein folding deficits as a disease mechanism (PMID:40222685).

These data define NSDHL haploinsufficiency via hypomorphic loss-of-function as the pathogenic mechanism underlying CK syndrome. The concordance of genetic segregation, phenotypic specificity in hemizygous males, and functional rescue in cellular and yeast models provides robust evidence for a Strong ClinGen clinical validity classification. Key Take-home: NSDHL mutation analysis should be integrated into diagnostic panels for X-linked intellectual disability, with potential therapeutic avenues targeting protein folding and sterol homeostasis.

References

• American journal of human genetics • 2010 • Hypomorphic temperature-sensitive alleles of NSDHL cause CK syndrome. PMID:21129721
• American journal of medical genetics. Part A • 2015 • A novel missense mutation in the NSDHL gene identified in a Lithuanian family by targeted next-generation sequencing causes CK syndrome. PMID:25900314
• The Journal of steroid biochemistry and molecular biology • 2025 • Comprehensive survey of disease-causing missense mutations of the cholesterol synthesis enzyme NSDHL: Low temperature and a chemical chaperone rescue low protein expression of select mutants. PMID:40222685

Evidence Based Scoring (AI generated)