Early onset or syndromic epilepsy

Gene: DHX16

Green List (high evidence)

Comment on list classification: There are at least 12 unrelated probands reported in literature with heterozygous missense variants in DHX16 (11 confirmed de novo). These individuals had a syndromic presentation, including hearing loss (8/12), retinopathy (9/12), and neuromuscular disease (9/12). 3 unrelated individuals presented with infantile spasms / epilepsy. Hence, this gene should be promoted to Green on Early onset or syndromic epilepsy at the next update.

Created: 13 Aug 2026, 10:44 a.m. | Last Modified: 13 Aug 2026, 10:44 a.m.

Panel Version: 9.57

PMID: 41555919 Wang et al., 2026
2 unrelated female probands with retinitis pigmentosa and sensorineural deafness. They each had heterozygous de novo variants in DHX16: NM_003587 c.2474C>T, p.Ser825Phe and NM_003587.5 c.1360C>T, p.Arg454Trp respectively. Case 1 presented with hypotonia; delayed motor development was noted in Case 2. Overall, no overt myopathy noted in these cases.

PMID: 40326698 Clay et al., 2025
3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. Trio WES detected a heterozygous de novo DHX16 variant, c.692G>C; p.R231P. Normal hearing, no hypotonia or myopathy. Authors argue the milder presentation may stem from this mutation being upstream of the functional helicase binding domain, where other variants were previously reported.

PMID: 40141454 Kalampokini et al., 2025
Report of a 36-year-old female with neuromuscular disease, sensorineural hearing loss (diagnosed at 13 months), retinitis pigmentosa, and primary ovarian insufficiency harboring a heterozygous de novo missense variant in DHX16 NM_003587.5:c.2032G>A, p (Glu678Lys) . She had gait difficulties with onset at 12 years; she became wheelchair bound at age 22 years. Visual symptoms (nyctalopia, photosensitivity, color, and peripheral vision problems) were noted at age 27 yrs. Her intellectual level was normal to high. Electromyography revealed changes compatible with myopathy, while NCS showed severe axonal sensorimotor peripheral polyneuropathy.

PMID: 37664979 Drackley et al., 2023
Report of a female proband. Profound bilateral sensorineural hearing loss noted at birth. Vision issues started early with nyctalopia, followed by severe cone- and rod-mediated disease (likely retinitis pigmentosa) diagnosis at 2 years of age. Hypotonia, motor delays, muscle weakness were present at 12–18 months of age. CMT testing uninformative.
Skeletal muscle biopsy showed myopathic changes, CK elevated at 1000 U/L. Trio exome and mitochondrial genome were uninformative. Trio WGS detected a de novo DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) variant.

PMID: 37574199 Hautakangas et al., 2023
Report of a female patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and moderate-to-severe sensorineural hearing loss. CK measurement = 1371 U/L. At the age of 3  years, the patient could move her hands and head but could not sit without support; progressive spasticity was noted. Patient harboured a de novo heterozygous c.1360C>T (p.Arg454Trp) variant in DHX16. Method: WES + Sanger seq in the parents.

PMID: 36211162 Archana et al., 2022
Male proband with bilateral severe hearing impairment noted at 4 months. He was not able to fixate on objects at 18 months. He had history of infantile spasms. Eye examination revealed nystagmus and bilateral retinal pigmentary mottling with amaurotic pupils - Leber's congenital amaurosis (LCA) was suspected. Clinical exome detected a heterozygous DHX16: c.1445G>A, p.Arg482His variant (inheritance unknown).

PMID: 36212160 Park et al., 2022
Korean proband harbouring DHX16 c.2021C > T, (p.Thr674Met) - de novo variant. Patient had congenital myopathy, with no ocular or audiologic symptoms reported.

PMID: 31256877 Paine et al., 2019
Report of 4 individuals with de novo heterozygous DHX16 missense variants (p.Gly427Glu, p.Phe582Ile, p.Thr674Met, p.Gln697His). Method: Trio Exome.
P6: Hypotonia; infantile spasms; Chorioretinal lacunae; depigmentation around optic nerve; poor visual tracking; Agenesis of CC.
P7: Small size; short limbs; dysmorphic facial features; enlarged, cystic kidneys - unusual presentation, het for p.Gln697His.
P8: Severe congenital hypotonia; denervating motor neuropathy; bilateral talipes equinovarus; nystagmus; SNHL.
P9: Myopathy with isolated necrotic fibers; elevated CK; abnormal gait; hypertrophic calf muscles; peripheral neuropathy; epilepsy; non-ambulation; Tapetoretinal degeneration and total vision loss; SNHL; contractures.

Created: 13 Aug 2026, 10:40 a.m. | Last Modified: 13 Aug 2026, 10:40 a.m.

Panel Version: 9.57

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neuromuscular disease and ocular or auditory anomalies with or without seizures, OMIM:618733 neuromuscular disease and ocular or auditory anomalies with or without seizures, MONDO:0032890

Publications

• 31256877
• 36212160
• 36211162
• 37574199
• 37664979
• 40141454
• 41555919

I don't know

Paine et al 2019 - 4 patients reported with de novo variants in DHX16. 2 of these have seizures as part of their phenotype, although the other two individuals died at 1 day and 4 months respectively.

Created: 29 Jan 2021, 2:13 p.m. | Last Modified: 29 Jan 2021, 2:13 p.m.

Panel Version: 2.280

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 31256877

I don't know

Associated with relevant phenotype in OMIM and as possible Gen2Phen gene for Intellectual Disability, Central Nervous System anomalies and Seizures. At least 4 variants reported as de novo heterozygous variants in 4 unrelated probands as a result of trio exome sequencing and seizures were reported in 2 of these cases. No functional studies were reported.
Sources: Literature

Created: 21 Sep 2020, 2:47 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Neuromuscular disease and ocular or auditory anomalies with or without seizures 618733

Publications

• 31256877