Constitutional genetics

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Constitutional genetics

Week of 29 April 2026

10 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►CDK5RAP3 — first human disease gene for a UFMylation adaptor: severe recessive lethal NDD (3 individuals, 2 families), full functional characterization including phosphoproteomics; add to severe recessive NDD panels.
►HNRNPH2 — first preclinical proof of ASO therapy efficacy in a mouse model of the X-linked NDD; sustained phenotypic correction — priority therapeutic avenue.
►SCN5A — a novel short transcript yields a NaV1.5 fragment regulating mitochondrial cardiac metabolism; a new mechanism of action for this cardinal cardiology gene.
►RNF216 — mechanism of Gordon-Holmes syndrome (HH + ataxia + dementia) elucidated: autophagy dysregulation via Beclin-1 in 1,476 screened HH patients.
►POR G88S — recurrent homozygous mutation in 4 unrelated Argentine families: severe PORD + high-risk pharmacogenomic profile established — worth flagging in MDT.
►NSUN3 — hypertrophic cardiomyopathy as novel manifestation of NSUN3 mitochondrial disease; systematic cardiac surveillance now warranted.
►MODY — first large population-based study on prevalence, penetrance and mortality for genetically confirmed MODY; key data for genetic counselling.
►SLC12A5/KCC2 — 2 new cases of severe neonatal-onset DEE; first demonstration that a variant can preserve ion transport while disrupting KCC2-dependent synaptogenesis (chloride-independent mechanism).

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A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3

Novel severe autosomal recessive neurodevelopmental syndrome linked to UFMylation

Acta Neuropathologica, online 2026-04-27· AprRead

XL de novoPubMed

Preclinical evaluation of antisense oligonucleotide therapy in a mouse model of HNRNPH2-related neurodevelopmental disorder

HNRNPH2-related NDD (X-linked, developmental delay, intellectual disability, motor disturbance)

Science Translational Medicine, 2026 Apr 22;18(846):eadx3491· AprRead

Compound heterozygous SLC12A5 variants expand the molecular and functional spectrum of KCC2-developmental and epileptic encephalopathy

KCC2-developmental and epileptic encephalopathy (KCC2-DEE) — severe neonatal EIMFS

Phenotypic expansionNew mechanism

Epilepsia, online ahead of print 2026· AprRead

Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism

Inherited cardiomyopathy / arrhythmia (Brugada, long QT, etc.) — new mechanism of action

Circulation Research, 2026 Apr 24;138(9):e326973· AprRead

RNF216 Variants Found in Patients With Dementia, Hypogonadotropic Hypogonadism, and Severe Ataxia Deregulate Autophagy

Gordon-Holmes syndrome (HH + severe ataxia + dementia — MIM#212840)

Journal of Clinical Endocrinology & Metabolism, 2026 Apr;111(5):1278-1286· AprRead

A Novel POR G88S Mutation Causes Severe PORD and Establishes a Critical Pharmacogenomic Risk Profile

P450 oxidoreductase deficiency (PORD — MIM#613571) — severe form

Recurrent variantFunctional SNV

Journal of Clinical Endocrinology & Metabolism, 2026 Apr;111(5):e1302-e1321· AprRead

A Novel MAP3K7 Variant Causing Loss of Function Identified in a Family With Cardiospondylocarpofacial Syndrome: Functional Validation and Molecular Insights

Cardiospondylocarpofacial syndrome (CSCF)

Human Mutation, 2026:8024677· AprRead

Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY

MODY (maturity-onset diabetes of the young) — population study

Phenotypic expansion

Journal of Clinical Endocrinology & Metabolism, 2026 Apr;111(5):e1388-e1395· AprRead

Hypertrophic cardiomyopathy as a novel phenotypic feature of NSUN3-related mitochondrial disease: a case report with review of the literature

NSUN3 mitochondrial disease + hypertrophic cardiomyopathy (phenotypic expansion)

Phenotypic expansion

Journal of Pediatric Endocrinology & Metabolism, 2026 Apr;39(4):372-380· AprRead

Meier-Gorlin syndrome due to a recurrent DONSON variant in a Turkish family: first report of thumb aplasia and long-term growth data

Meier-Gorlin syndrome (MGORS — primordial dwarfism) — phenotypic expansion

PrenatalPhenotypic expansionRecurrent variant

Journal of Pediatric Endocrinology & Metabolism, 2026 Apr;39(4):388-395· AprRead

References and sources

CDK5RAP3 — Novel severe autosomal recessive neurodevelopmental syndrome linked to UFMylation. Acta Neuropathologica, online 2026-04-27. PMID 42045457. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42045457/
HNRNPH2 — HNRNPH2-related NDD (X-linked, developmental delay, intellectual disability, motor disturbance). Science Translational Medicine, 2026 Apr 22;18(846):eadx3491. PMID 42018666. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42018666/
SCN5A — Inherited cardiomyopathy / arrhythmia (Brugada, long QT, etc.) — new mechanism of action. Circulation Research, 2026 Apr 24;138(9):e326973. PMID 41808628. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/41808628/
RNF216 — Gordon-Holmes syndrome (HH + severe ataxia + dementia — MIM#212840). Journal of Clinical Endocrinology & Metabolism, 2026 Apr;111(5):1278-1286. PMID 41271602. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/41271602/
POR — P450 oxidoreductase deficiency (PORD — MIM#613571) — severe form. Journal of Clinical Endocrinology & Metabolism, 2026 Apr;111(5):e1302-e1321. PMID 41258701. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/41258701/
MAP3K7 — Cardiospondylocarpofacial syndrome (CSCF). Human Mutation, 2026:8024677. PMID 42040894. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42040894/
HNF1A — MODY (maturity-onset diabetes of the young) — population study. Journal of Clinical Endocrinology & Metabolism, 2026 Apr;111(5):e1388-e1395. PMID 41175096. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41175096/
NSUN3 — NSUN3 mitochondrial disease + hypertrophic cardiomyopathy (phenotypic expansion). Journal of Pediatric Endocrinology & Metabolism, 2026 Apr;39(4):372-380. PMID 41725275. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41725275/
DONSON — Meier-Gorlin syndrome (MGORS — primordial dwarfism) — phenotypic expansion. Journal of Pediatric Endocrinology & Metabolism, 2026 Apr;39(4):388-395. PMID 41612845. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/41612845/
SLC12A5 — KCC2-developmental and epileptic encephalopathy (KCC2-DEE) — severe neonatal EIMFS. Epilepsia, online ahead of print 2026. PMID 42033187. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42033187/