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Constitutional genetics

Week of 11 August 2026

15 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►ELAVL2 — 16 individuals with de novo heterozygous variants, haploinsufficiency supported by Drosophila models, population data and reduced protein levels.
►AIRE — the variant effect map of 9,790 missense variants provides functional evidence for 70% of reported VUS and resolves 32% of them.
►De novo mutations — across 24,030 individuals with whole-genome sequencing, ICSI and ovarian stimulation increase paternal and maternal de novo variants respectively, independently of age.
►AP5B1 — the recurrent missense variant p.(Leu785Pro) is found in 22 patients from 20 families, homozygous in 16 of them, with hearing loss in 8 patients.
►CHD8 — the episignature reclassifies 8 of the 36 missense variants analysed as likely pathogenic, where detailed phenotyping discriminated nothing.

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Autosomal dominantPubMed

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

ELAVL2-related neurodevelopmental disorder

NeurodevelopmentNew geneFunctional SNV

Am J Hum Genet 2026· AugRead

Systematic and proactive evaluation of AIRE missense variant effects.

Autoimmune polyendocrine syndrome type 1

VUS reclassifiedFunctional SNV

Am J Hum Genet 2026· AugRead

WGS / Diagnosis

Large-scale whole-genome sequencing reveals the landscape and health implications of de novo mutations.

De novo mutations, parental age and assisted reproductive technology

WGS / Diagnosis

Nat Med 2026· AugRead

WGS / Diagnosis

The British Society for Genetic Medicine guidance on managing incidental findings identified during rare disease genomic testing.

Incidental findings in rare disease genomic testing

WGS / Diagnosis

J Med Genet 2026· AugRead

Autosomal recessivePubMed

The AP5B1 p.(Leu785Pro) variant is a frequent cause of late-onset macular dystrophy with variable extraocular manifestations.

AP5B1-related late-onset macular dystrophy

Recurrent variantPhenotypic expansion

HGG Adv 2026· AugRead

Autosomal dominantPubMed

An episignature informed systematic analysis to ascertain the clinical significance and consequences of CHD8 missense variants.

Intellectual developmental disorder with autism and macrocephaly

NeurodevelopmentVUS reclassified

Eur J Hum Genet 2026· AugRead

Autosomal recessivePubMed

CCDC149: a novel gene associated with hypopituitarism and neurodevelopmental impairment.

Congenital hypopituitarism

NeurodevelopmentNew geneFunctional SNV

Eur J Endocrinol 2026· AugRead

WGS / Diagnosis

Autosomal recessivePubMed

Whole-exome sequencing in undiagnosed muscular dystrophies: a high diagnostic yield and novel insights from Iranian families.

Non-dystrophinopathic muscular dystrophies

WGS / Diagnosis

Hum Mutat 2026· AugRead

Reclassification of genetic variants in patients with hypertrophic cardiomyopathy from the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Hypertrophic cardiomyopathy

CardiologyVUS reclassified

medRxiv 2026· AugRead

Rapid genomic sequencing in the NICU: who to test and why.

Rapid genomic sequencing in the neonatal intensive care unit

Eur J Hum Genet 2026· AugRead

Autosomal dominantmedRxiv

Truncated ASXL3 alters chromatin accessibility and epigenetic landscape in Bainbridge-Ropers syndrome suggesting a gain-of-function etiology

Bainbridge-Ropers syndrome

NeurodevelopmentNew mechanismFunctional SNV

medRxiv 2026· AugRead

Autosomal recessivePubMed

TTC14 dysfunction contributing to microcephaly and lissencephaly spectrum features through protein mislocalization and impaired RNA processing.

Microcephaly and lissencephaly spectrum

NeurodevelopmentNew geneFunctional SNV

Hum Genet 2026· AugRead

WGS / Diagnosis

Tandem repeat expansions in DAPK1, ANK3, and RPL14 are associated with diverse neurodegenerative diseases

Neurodegenerative disease and tandem repeat expansions

WGS / DiagnosisRepeat expansion

medRxiv 2026· AugRead

Dominant lié à l'XPubMed

Surviving males with PORCN variants: expanding the clinical, molecular, and mechanistic spectrum.

Focal dermal hypoplasia (Goltz syndrome)

Phenotypic expansion

Clin Genet 2026· AugRead

Autosomal recessivePubMed

Homozygous missense variants in CACNB4 underlie autosomal recessive epilepsy in two unrelated Pakistani consanguineous families.

Autosomal recessive epilepsy

Metabolism / Epilepsy

Seizure 2026· AugRead

References and sources

ELAVL2 — ELAVL2-related neurodevelopmental disorder. Am J Hum Genet 2026. PMID 42556336. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42556336/
AIRE — Autoimmune polyendocrine syndrome type 1. Am J Hum Genet 2026. PMID 42561935. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42561935/
De novo mutations, parental age and assisted reproductive technology. Nat Med 2026. PMID 42567929. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42567929/
Incidental findings in rare disease genomic testing. J Med Genet 2026. PMID 42562627. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42562627/
CCDC149 — Congenital hypopituitarism. Eur J Endocrinol 2026. PMID 42554577. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42554577/
ASXL3 — Bainbridge-Ropers syndrome. medRxiv 2026. doi:10.64898/2026.08.04.26359647. Score 5/10. https://www.medrxiv.org/content/10.64898/2026.08.04.26359647v1
TTC14 — Microcephaly and lissencephaly spectrum. Hum Genet 2026. PMID 42572047. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42572047/
AP5B1 — AP5B1-related late-onset macular dystrophy. HGG Adv 2026. PMID 42568187. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42568187/
Non-dystrophinopathic muscular dystrophies. Hum Mutat 2026. PMID 42553504. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42553504/
Neurodegenerative disease and tandem repeat expansions. medRxiv 2026. doi:10.64898/2026.08.06.26358503. Score 5/10. https://www.medrxiv.org/content/10.64898/2026.08.06.26358503v1
Hypertrophic cardiomyopathy. medRxiv 2026. doi:10.64898/2026.08.05.26359735. Score 6/10. https://www.medrxiv.org/content/10.64898/2026.08.05.26359735v1
Rapid genomic sequencing in the neonatal intensive care unit. Eur J Hum Genet 2026. PMID 42562942. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42562942/
CACNB4 — Autosomal recessive epilepsy. Seizure 2026. PMID 42570371. Score 4/10. https://pubmed.ncbi.nlm.nih.gov/42570371/
CHD8 — Intellectual developmental disorder with autism and macrocephaly. Eur J Hum Genet 2026. PMID 42575949. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42575949/
PORCN — Focal dermal hypoplasia (Goltz syndrome). Clin Genet 2026. PMID 42575871. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42575871/