DHX9

Chr 1

DExH-box helicase 9

Also known as: DDX9, LKP, MRD75, NDH2, NDHII, RHA

NCBI Gene: 1660 ENSG00000135829 UniProt: Q08211

The DHX9 protein is an ATP-dependent helicase that unwinds double-stranded RNA and DNA-RNA complexes and functions as a transcriptional regulator involved in DNA replication, RNA processing, and gene expression. Mutations cause autosomal dominant intellectual developmental disorder. This gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.105), indicating that even heterozygous loss is likely to be pathogenic.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the DEAH-containing family of RNA helicases. The encoded protein is an enzyme that catalyzes the ATP-dependent unwinding of double-stranded RNA and DNA-RNA complexes. This protein localizes to both the nucleus and the cytoplasm and functions as a transcriptional regulator. This protein may also be involved in the expression and nuclear export of retroviral RNAs. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 11 and 13.[provided by RefSeq, Feb 2010]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.10

Clinical Summary— DHX9

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 121 VUS of 197 total submissions

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GeneReview available — DHX9

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 7.62

OE 0.04 (0.02–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.84Z-score

OE missense 0.38 (0.34–0.42)

264 obs / 698.6 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.10)

0≤0.351.4

Missense OE?0.38 (0.34–0.42)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 73.6Missense obs/exp: 264 / 698.6Syn Z: -1.21

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateDHX9-related neurodevelopmental disorder and Charcot-Marie-Tooth diseaseLOFAD

This gene — mechanism propensity

0.2897th %ile

GOF

0.3590th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 71% of P/LP variants are LoF · LOEUF 0.10

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

197 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic7

VUS121

Likely Benign16

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

121

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	1	0	0	10
Likely Pathogenic	3	4	0	0	7
VUS	9	111	1	0	121
Likely Benign	0	4	2	10	16
Benign	0	0	1	2	3
Conflicting	—				1
Total	21	120	4	12	158

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

28 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap DHX9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →