NSDHL

protein-coding

NAD(P) dependent steroid dehydrogenase-like, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

The protein encoded by this gene is localized in the endoplasmic reticulum and is involved in cholesterol biosynthesis. Mutations in this gene are associated with CHILD syndrome, which is a X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, and typically lethal in males. Alternatively spliced transcript variants with differing 5' UTR have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015922.3

Inheritance

ClinVar variants

P:21U:165B:100

Top phenotype

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome); CK syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:152,830,967-152,869,729

External References & Databases

Ensembl (ENSG00000147383)

Transcript & Mutation Effects

hg38 • Region Span ~38.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

CK syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010441

Submitter: Labcorp Genetics (formerly Invitae)

CHILD syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010621

Submitter: G2P

CHILD syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010621

Submitter: Orphanet

CK syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010441

Submitter: Orphanet

CHILD syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010621

Submitter: Labcorp Genetics (formerly Invitae)

CK syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010441

Submitter: G2P

CHILD syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010621

Submitter: PanelApp Australia

CK syndromeMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010441

Submitter: ClinGen

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).

CHILD syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010621

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome); CK syndromeXL

Manifestation: Cardiovascular; Dermatologic; Musculoskeletal; Pulmonary; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 5696317; 7408908; 8882402; 10710233; 10710235; 11907515; 12966526; 19842190; 19377476; 20605772; 21129721; 21290788

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NSDHL variants in ClinVar

22 Conditions Cataloged

not providedTotal: 196

Child syndromeTotal: 54

not specifiedTotal: 49

CK syndromeTotal: 44

Inborn genetic diseasesTotal: 40

NSDHL-related disorderTotal: 20

Connective tissue disorderTotal: 7

Intellectual disabilityTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015922.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			17 clinvar	44 clinvar	11 clinvar	72
missense	2 clinvar	7 clinvar	127 clinvar	39 clinvar	6 clinvar	181
nonsense	6 clinvar		5 clinvar			11
start loss						0
frameshift	3 clinvar	2 clinvar				5
splice donor/acceptor (+/-2bp)		1 clinvar	16 clinvar			17
Total	11	10	165	83	17	286

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015922.3	RefSeq	NP_057006.1	7	MANE Select
ENST00000370274.8	Ensembl	ENSP00000359297.3	7	MANE Select
NM_001129765.2	RefSeq	NP_001123237.1	7	Standard
NM_001441099.1	RefSeq	NP_001428028.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Steroid biosynthesis - Homo sapiens (human)
Simvastatin Action Pathway
Pravastatin Action Pathway
Atorvastatin Action Pathway
Hyper-IgD syndrome

Biological Process

hair follicle development
cholesterol biosynthetic process
smoothened signaling pathway
cholesterol metabolic process
oxidation-reduction process

Molecular Function

C-3 sterol dehydrogenase (C-4 sterol decarboxylase) activity
3-beta-hydroxy-delta5-steroid dehydrogenase activity
oxidoreductase activity
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
sterol-4-alpha-carboxylate 3-dehydrogenase (decarboxylating) activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
lipid droplet
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370274
Coding exons: 7
Length: 38763
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.869	124	154	0.803	0.0000124	2453
Missense (PolyPhen)		22	50.608	0.43471		827
Synonymous	-1.02	74	63.7	1.16	0.00000545	740
Loss of Function	2.98	0	10.3	0.00	7.28e-7	179

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. {ECO:0000269|PubMed:14506130}.;
Disease: DISEASE: CK syndrome (CKS) [MIM:300831]: A disorder characterized by mild to severe cognitive impairment, seizures, microcephaly, cerebral cortical malformations, dysmorphic facial features, and thin body habitus. {ECO:0000269|PubMed:21129721}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.189

Intolerance Scores

RVIS EVS: -0.2
RVIS percentile EVS: 38.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.655

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium