Constitutional genetics

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Constitutional genetics

Week of 6 May 2026

14 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►DSCAM — new recessive NDD gene: biallelic LOF variants in consanguineous individuals → NDD + nystagmus + retinal dysfunction; add to recessive NDD panels.
►TRIO — phenotypic expansion: de novo missense variant in Ras-GEF domains → congenital ventriculomegaly/hydrocephalus.
►PMP22 deep intronic variant + targeted ASO correction: exome-missed diagnosis resolved by WGS + functional correction demonstrated — theranostic model for hereditary neuropathies.
►SNX14 — pseudo-exon activated by deep intronic variant → SCAR20; highlights the critical value of WGS in unresolved post-exome cases.
►FGF14 SCA27B — Spanish cohort + long-term aminopyridine response: strong clinical argument for systematic genotyping in downbeat nystagmus ataxia.
►TNRC6B — phenotypic expansion across 3 generations with 22q11 locus; inter- and intrafamilial variability demonstrated for this RISC-essential gene.
►SYNJ1 biallelic → MSA-mimic syndrome: major clinical expansion, include SYNJ1 in workup of atypical parkinsonian syndromes.
►ALDH7A1/PDE-ALDH7A1 — classical and emerging biomarkers of this treatable epilepsy: α-AASA, P6C, lysine, pipecolic acid — guide therapeutic monitoring.
►LMNA/FLNC/RBM20/PLN — ESC 2023 guidelines redefine ICD indications in high-risk arrhythmia cardiomyopathies beyond LVEF alone.
►OTC cryptic variants — 2 cases with synonymous/in-frame variants resolved by functional RNA analysis; highlights diagnostic limits of standard tools for non-canonical variants.
►MAGED2 — 3 novel variants in 3 Chinese families → transient antenatal Bartter syndrome; complete prenatal/postnatal characterization of this X-linked gene.
►Prenatal WGS for fetal anomalies — diagnostic yield exceeds exome+CMA combination in recent series; NHS implementation challenges on the clinical agenda.
►First-tier WGS — Danish cohort (2,317 patients, EJHG 2026): diagnostic yield stratified by specialty, European benchmark directly applicable to AURAGEN/SEQOIA context.

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Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction

Novel autosomal recessive NDD: intellectual disability, nystagmus and retinal dysfunction

NeurodevelopmentNew gene

HGG Advances, 2026· AprRead

AD de novoPubMed

De Novo TRIO Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus

Congenital ventriculomegaly/hydrocephalus and neurodevelopmental disorder

NeurodevelopmentPhenotypic expansion

Human Mutation, 2026Read

Identification and Targeted Correction of a Pathogenic PMP22 Deep Intronic Variant

Hereditary demyelinating peripheral neuropathy (CMT1E / HNPP)

NeurologyFunctional SNV

International Journal of Molecular Sciences, 2026· AprRead

A Homozygous Deep Intronic SNX14 Variant Activates Pseudo-Exon Inclusion in a Patient with SCAR20

SCAR20 (autosomal recessive spinocerebellar ataxia type 20)

NeurologyFunctional SNV

Genes (Basel), 2026· MarRead

Short-read genome sequencing at population scale: diagnostic insights from 2317 patients

Genetic diseases across all specialties — real-world first-tier WGS benchmark (Denmark)

NeurodevelopmentDiagnostic yield

European Journal of Human Genetics, 2026· MarRead

AD (expansion répétition)PubMed

Long-term response to aminopyridines in a cohort of patients with ataxia associated with downbeat nystagmus due to the FGF14 GAA expansion

SCA27B — cerebellar ataxia with downbeat nystagmus (A-DBN)

NeurologyPhenotypic expansion

Neurologia (Engl Ed), 2026· MayRead

Expansion of the Phenotypic Spectrum of TNRC6B-Related Neurodevelopmental Disorder in a Three-Generation Family with 22q11 Region

Neurodevelopmental disorder with inter- and intrafamilial phenotypic variability

NeurodevelopmentPhenotypic expansion

Genes (Basel), 2026· AprRead

Functional and Expression Studies of iPSC-Derived Cardiomyocytes Carrying a Novel HCM-Associated MYPN Genetic Variant

Familial hypertrophic cardiomyopathy (HCM)

CardiologyFunctional SNV

Genes (Basel), 2026· AprRead

Biallelic SYNJ1 Variants in a patient with multiple system atrophy mimic syndrome

Atypical parkinsonian syndrome mimicking multiple system atrophy (MSA-like)

NeurologyPhenotypic expansion

Neurological Sciences, 2026· MayRead

Classical and Emerging Biomarkers in Pyridoxine-Dependent Epilepsy (PDE-ALDH7A1): Implications for Early Diagnosis and Therapy

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) — treatable epileptic encephalopathy

Metabolism / EpilepsyNew mechanism

Biomolecules, 2026· MarRead

High-Risk Cardiomyopathy Genotypes and Arrhythmic Risk: LMNA, FLNC, RBM20, PLN and Desmosomal Genes in the ESC 2023 Era

Hereditary cardiomyopathies (HCM, DCM) with high risk of ventricular arrhythmia and sudden death

CardiologyPhenotypic expansion

Genes (Basel), 2026· MarRead

Pedigree and Functional Analysis of Two Cryptic OTC Variants Causing Ornithine Transcarbamylase Deficiency in Two Unrelated Families

Ornithine transcarbamylase deficiency (OTCD, MIM#311250) — urea cycle disorder

Metabolism / EpilepsyFunctional SNV

Molecular Genetics & Genomic Medicine, 2026· MayRead

Identification of Three Novel MAGED2 Variants Causing Antenatal Bartter Syndrome in Three Chinese Families

Transient antenatal Bartter syndrome (TABS) — X-linked fetal salt-losing syndrome

PrenatalRecurrent variant

Genes (Basel), 2026· AprRead

Prenatal Whole-Genome Sequencing for Fetal Anomalies: Diagnostic Performance, Challenges, and Clinical Implications

Fetal anomalies (aneuploidies, CNVs, SNVs, structural variants, regions of absence of heterozygosity)

PrenatalPhenotypic expansion

International Journal of Molecular Sciences, 2026· AprRead

References and sources

DSCAM — Novel autosomal recessive NDD: intellectual disability, nystagmus and retinal dysfunction. HGG Advances, 2026. PMID 42063257. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42063257/
TRIO — Congenital ventriculomegaly/hydrocephalus and neurodevelopmental disorder. Human Mutation, 2026. PMID 42051466. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42051466/
PMP22 — Hereditary demyelinating peripheral neuropathy (CMT1E / HNPP). International Journal of Molecular Sciences, 2026. PMID 42074212. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42074212/
SNX14 — SCAR20 (autosomal recessive spinocerebellar ataxia type 20). Genes (Basel), 2026. PMID 42074495. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42074495/
FGF14 — SCA27B — cerebellar ataxia with downbeat nystagmus (A-DBN). Neurologia (Engl Ed), 2026. PMID 42044943. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42044943/
TNRC6B — Neurodevelopmental disorder with inter- and intrafamilial phenotypic variability. Genes (Basel), 2026. PMID 42074582. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42074582/
MYPN — Familial hypertrophic cardiomyopathy (HCM). Genes (Basel), 2026. PMID 42074575. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42074575/
SYNJ1 — Atypical parkinsonian syndrome mimicking multiple system atrophy (MSA-like). Neurological Sciences, 2026. PMID 42067721. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42067721/
ALDH7A1 — Pyridoxine-dependent epilepsy (PDE-ALDH7A1) — treatable epileptic encephalopathy. Biomolecules, 2026. PMID 42072608. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42072608/
LMNA — Hereditary cardiomyopathies (HCM, DCM) with high risk of ventricular arrhythmia and sudden death. Genes (Basel), 2026. PMID 42074488. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42074488/
OTC — Ornithine transcarbamylase deficiency (OTCD, MIM#311250) — urea cycle disorder. Molecular Genetics & Genomic Medicine, 2026. PMID 42050797. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42050797/
MAGED2 — Transient antenatal Bartter syndrome (TABS) — X-linked fetal salt-losing syndrome. Genes (Basel), 2026. PMID 42074542. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42074542/
Fetal anomalies (aneuploidies, CNVs, SNVs, structural variants, regions of absence of heterozygosity). International Journal of Molecular Sciences, 2026. PMID 42074207. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42074207/
WGS Clinique — Genetic diseases across all specialties — real-world first-tier WGS benchmark (Denmark). European Journal of Human Genetics, 2026. PMID 41917265. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/41917265/