NSDHL-Related Disorders via the NSDHL Gene

NSDHL-related disorders include two distinct allelic diseases: CHILD (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) syndrome and CK syndrome. CHILD syndrome is a rare X-linked dominant birth defect. Less than 100 cases have been identified. Classic clinical features include unilateral and sharply demarcated skin ichthosiform nevus and distinctive limb hypoplasia or aplasia on the same side as the skin lesion. Intelligence is usually normal. Visceral involvement is commonly found in severe cases. Central nervous system malformations and mild cognitive problems have also been reported. CHILD syndrome is usually male-lethal during gestation with few exceptions, likely due to the presence of mosaicism (Souich et al. 2013; König et al. 2000; Bornholdt et al. 2005).

CK syndrome, named after the initial proband, is an X-linked recessive intellectual disability syndrome. To date, CK syndrome segregating in males has been described in two unrelated families. All 13 reported male patients have mild to severe cognitive impairment, seizures in infancy, microcephaly, cerebral cortical malformations, characteristic craniofacial features, a thin habitus, and behavior problems (aggression, hyperactivity, and irritability) (McLarren et al. 2010).

The NSDHL gene is located on chromosome Xq28 and consists of 7 coding exons. NSDHL encodes a sterol dehydrogenase that forms a complex with two other enzymes to remove C4 methyl groups in postsqualene cholesterol biosynthesis.

CHILD syndrome is an X-linked dominant disorder caused by loss-of-function mutations in the NSDHL gene. A total of ~20 mutations have been identified including three gross deletions, two splicing mutations, one frameshift mutation, 7 nonsense and 9 missense mutations. Most reported female patients are sporadic, although mother-to-daughter transmission has been reported in a few families (Bornholdt et al 2005). The penetrance is expected to be very high, and random X-inactivation is presumed to account for variable expressivity observed in affected female family members (Souich et al. 2013).

CK syndrome is inherited as an X-linked recessive disorder caused by hypomorphic NSDHL mutations that result in a partial loss of enzyme function. To date, only two unrelated families have been reported, and one of two mutations (c.696_698delGAA, p.Lys232del and c.1098dupT, p.Arg367SerfsX33) was identified in all affected males (McLarren et al. 2010). No other CK syndrome-associated mutations have been reported.

NSDHL is the only gene known to be causative for CHILD syndrome or CK syndrome. In a cohort of 23 patients with CHILD syndrome, sequence analysis of all NSDHL coding regions identified about 90% of all pathogenic variants (Bornholdt et al. 2005).

Deletion/duplication analysis is expected to account for ~10% of CHILD syndrome associated mutations (Souich et al. 2013). Three gross deletions affecting the NSDHL gene have been reported so far.

This test provides full coverage of all coding exons of the NSDHL gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).