Constitutional genetics

Week of 27 October 2026

17 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►PLAAT4 — new dominant leukodystrophy gene: 26 patients from 11 families, "girdle-like" spinal cord hyperintensity and a diagnostic pitfall with multiple sclerosis.
►SRSF3 — new neurodevelopmental disorder gene: de novo variants in 9 patients, with distinct functional defects depending on variant type.
►KCNQ1 — functional map of 13,403 variants: strong pathogenic evidence for 1757 of them, and dominant-negative effects linked to higher arrhythmia risk.
►OTOF — functional reclassification of 8 variants of uncertain significance yields 38 diagnoses and opens gene therapy to 7 patients.
►EP400 — a coding CAG expansion, a new cause of spinocerebellar ataxia in 18 Serbian patients from 14 families (preprint).

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Autosomal dominantPubMed

Gain-of-Function Variants in PLAAT4 and Spinal Predominant Demyelinating Leukodystrophy.

Spinal predominant demyelinating leukodystrophy with leg spasticity (SPDMLS)

NeurologyNew geneFunctional SNV

JAMA Neurol 2026· OctRead

De novo variants in the essential splicing factor gene SRSF3 cause variable developmental phenotypes.

Neurodevelopmental disorder with developmental delay and intellectual disability

NeurodevelopmentNew geneFunctional SNV

Am J Hum Genet 2026· OctRead

Multimodal KCNQ1 Variant-Effect Maps Define Ion Channel Mechanisms and Disease Risk.

Congenital long QT syndrome

Circulation 2026· OctRead

A Recurrent 3'UTR Variant in CAPN3 Highlights the Diagnostic Impact of Non-Coding Variants in Limb-Girdle Muscular Dystrophies.

CAPN3-related limb-girdle muscular dystrophy and persistent hyperCKemia

Recurrent variantFunctional SNV

Ann Neurol 2026· OctRead

Autosomal recessivePubMed

Genetic and Clinical Characterization of Early-Onset High Myopia With or Without Cataract Due to Biallelic P3H2 Variants.

Early-onset high myopia with or without cataract

Recurrent variant

Invest Ophthalmol Vis Sci 2026· OctRead

A translational pipeline for classification of variants of uncertain significance to support gene therapy clinical trial in OTOF-related deafness.

OTOF-related congenital deafness

VUS reclassifiedFunctional SNV

Cell Rep Med 2026· OctRead

Genetic and functional analysis of CDH2 reveals new insights into CDH2-related disorders.

ACOGS (agenesis of the corpus callosum, cardiac, ocular and genital syndrome)

Phenotypic expansion

Genet Med 2026· OctRead

Deep intronic NIPBL variants underlie unresolved Cornelia de Lange syndrome revealed by integrated epigenomic and transcriptomic analysis.

Cornelia de Lange syndrome

WGS / DiagnosisDeep intronic variantFunctional SNV

Eur J Hum Genet 2026· OctRead

Extended Non-Invasive Prenatal Testing for Chromosomal and Monogenic Disorders by Cell-Free DNA Sequencing: A Blinded Comparison With Amniocentesis.

Fetal chromosomal and monogenic disorders

PrenatalPrenatal application

Prenat Diagn 2026· OctRead

Nationwide Implementation of Newborn Screening for Spinal Muscular Atrophy in Canada.

Spinal muscular atrophy

Newborn screening

Neurol Genet 2026· OctRead

Loss-of-function variants in CFAP57, SEPTIN4, SPEM2, and CFAP46 cause asthenoteratozoospermia.

Asthenoteratozoospermia and male infertility

Phenotypic expansionFunctional SNV

Hum Reprod 2026· OctRead

Autosomal recessivePubMed

Loss of RUBCN causes autophagy overdrive in a neurodevelopmental disorder with age-dependent neurodegeneration.

Neurodevelopmental disorder with age-dependent neurodegeneration (SCAR15 spectrum)

NeurodevelopmentPhenotypic expansionFunctional SNV

medRxiv 2026· SepRead

A coding CAG repeat expansion in EP400 causes Spinocerebellar Ataxia

Spinocerebellar ataxia

NeurologyRepeat expansionPhenotypic expansion

medRxiv 2026· OctRead

Autosomal dominantPubMed

Population-based genomic screening of FGFR3 reveals variant spectrum, disease burden and clinical outcomes in 39,104 newborns.

FGFR3-related skeletal dysplasias (Muenke syndrome, hypochondroplasia)

Newborn screening

Bone 2026· OctRead

WGS / Diagnosis

Characterization of de novo structural variants in trios with orofacial clefts

Orofacial clefts

WGS / Diagnosis

medRxiv 2026· OctRead

Autosomal dominant et autosomal recessivePubMed

Double trouble in hereditary spastic paraplegia: revisiting the classical inheritance model.

Hereditary spastic paraplegia

Rev Neurosci 2026· OctRead

WGS / Diagnosis

The average individual genome: a survey of nearly 1 million whole-genome sequences.

Genomic variation in the general population

WGS / Diagnosis

Genome Med 2026· OctRead

References and sources

PLAAT4 — Spinal predominant demyelinating leukodystrophy with leg spasticity (SPDMLS). JAMA Neurol 2026. PMID 42931738. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42931738/
SRSF3 — Neurodevelopmental disorder with developmental delay and intellectual disability. Am J Hum Genet 2026. PMID 42901169. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42901169/
KCNQ1 — Congenital long QT syndrome. Circulation 2026. PMID 42899351. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42899351/
CAPN3 — CAPN3-related limb-girdle muscular dystrophy and persistent hyperCKemia. Ann Neurol 2026. PMID 42904565. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42904565/
P3H2 — Early-onset high myopia with or without cataract. Invest Ophthalmol Vis Sci 2026. PMID 42924990. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42924990/
OTOF — OTOF-related congenital deafness. Cell Rep Med 2026. PMID 42843343. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42843343/
CDH2 — ACOGS (agenesis of the corpus callosum, cardiac, ocular and genital syndrome). Genet Med 2026. PMID 42924497. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42924497/
NIPBL — Cornelia de Lange syndrome. Eur J Hum Genet 2026. PMID 42897219. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42897219/
Fetal chromosomal and monogenic disorders. Prenat Diagn 2026. PMID 42900896. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42900896/
SMN1 — Spinal muscular atrophy. Neurol Genet 2026. PMID 42899123. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42899123/
CFAP46 — Asthenoteratozoospermia and male infertility. Hum Reprod 2026. PMID 42906914. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42906914/
RUBCN — Neurodevelopmental disorder with age-dependent neurodegeneration (SCAR15 spectrum). medRxiv 2026. PMID 42922613. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42922613/
EP400 — Spinocerebellar ataxia. medRxiv 2026. doi:10.64898/2026.10.16.26365393. Score 6/10. https://www.medrxiv.org/content/10.64898/2026.10.16.26365393v1
FGFR3 — FGFR3-related skeletal dysplasias (Muenke syndrome, hypochondroplasia). Bone 2026. PMID 42913872. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42913872/
Orofacial clefts. medRxiv 2026. doi:10.64898/2026.10.16.26365772. Score 6/10. https://www.medrxiv.org/content/10.64898/2026.10.16.26365772v1
Hereditary spastic paraplegia. Rev Neurosci 2026. PMID 42905489. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42905489/
Genomic variation in the general population. Genome Med 2026. PMID 42907903. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42907903/

20 October 2026