DHX30 – Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language

DHX30 encodes a DExH-box RNA helicase whose heterozygous de novo variants have been causally linked to neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) (MONDO:0060622). Affected individuals present with global developmental delay, severe speech impairment, gait abnormalities, hypotonia, facial dysmorphism, sleep disturbances, feeding difficulties, and variable seizures.

Inheritance is autosomal dominant with consistent de novo occurrence of missense variants within helicase core motifs. Initial reports identified six distinct heterozygous missense mutations in 12 unrelated probands (PMID:29100085). Subsequent studies described a Japanese adult and two girls with novel de novo HCM missense variants (PMID:34145223), a Korean family with two affected siblings harboring the c.2344C>T (p.Arg782Trp) variant (PMID:37094863), and a 12-year-old female with c.2387C>T (p.Pro796Leu) (PMID:36643085). Including 25 additional individuals from functional cohort studies, the collective data comprise over 50 independent probands and recurrent alleles.

Segregation analysis in the Korean family demonstrated two affected siblings carrying the same de novo variant absent in parental samples, consistent with germline mosaicism and familial recurrence (PMID:37094863). No evidence of unaffected carriers has been reported.

Functional assays have shown that HCM missense variants abolish ATPase and helicase activity, trigger aberrant stress granule formation, and inhibit global translation. CRISPR/Cas9 DHX30-deficient HEK293T cells and zebrafish models recapitulate key human phenotypes, including developmental defects and altered sleep-wake behavior (PMID:34020708). Truncating and haploinsufficiency variants result in a milder clinical presentation, supporting a distinct loss-of-function mechanism for non-HCM alleles.

Collectively, extensive case series, segregation data, and concordant functional studies fulfill ClinGen criteria for a Definitive gene–disease relationship. Genetic testing for DHX30 for patients with unexplained severe motor impairment and absent language is recommended for accurate diagnosis and management.

Key take-home: DHX30 de novo HCM missense variants are definitively associated with NEDMIAL; functional assays and model organisms robustly validate pathogenicity, supporting clinical testing.

References

• American Journal of Human Genetics • 2017 • De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder PMID:29100085
• Genome Medicine • 2021 • Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders PMID:34020708
• Human Genome Variation • 2021 • A Japanese adult and two girls with NEDMIAL caused by de novo missense variants in DHX30 PMID:34145223
• Cureus • 2023 • A Novel De Novo Mutation of the DHX30 Gene in a Patient With Neurodevelopmental Disorder, Severe Motor Impairment, and Absent Language (NEDMIAL) PMID:36643085
• Annals of Clinical and Laboratory Science • 2023 • DHX30-Associated Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language: First Korean Case in Two Siblings and Literature Review PMID:37094863

Evidence Based Scoring (AI generated)