Constitutional genetics

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Constitutional genetics

Week of 20 May 2026

16 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►KMT2D — next-generation episignature: 97% sensitivity for Kabuki syndrome VUS classification, with fine mapping of pathogenic regions in exon 48.
►TSC1/TSC2 — 46% apparent penetrance in 900,000 adults: the near-complete penetrance dogma for tuberous sclerosis is challenged, with direct implications for genomic newborn screening.
►COL1A1/COL1A2 — 40% and 21% penetrance in the general population: current ClinVar assertions may overstate osteogenesis imperfecta risk for missense variants in screening contexts.
►RAC1 switch II — two opposing mechanisms (activating vs dominant-negative) based on position within the domain, determining two distinct phenotypes (normocephaly vs microcephaly).
►NF1 mosaic — first reciprocal translocation identified by optical genome mapping in cultured melanocytes, where WES had failed.

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Autosomal dominantPubMed

A next-generation episignature for Kabuki syndrome enables fine mapping of the impact of KMT2D variants to inform precision medicine.

Kabuki syndrome type 1

NeurodevelopmentVUS reclassifiedLong-read sequencing

American Journal of Human Genetics 2026· MayRead

Autosomal dominantPubMed

Uncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening.

Tuberous sclerosis complex

Newborn screeningPenetrance updatePrenatal application

European Journal of Human Genetics 2026· MayRead

Autosomal dominantPubMed

Reduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort.

Osteogenesis imperfecta

Newborn screeningPenetrance updatePrenatal application

European Journal of Human Genetics 2026· MayRead

Autosomal dominantPubMed

Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1.

RAC1-related neurodevelopmental disorder

NeurodevelopmentPhenotypic expansionFunctional SNV

European Journal of Human Genetics 2026· MayRead

EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders.

RYR1-related disorders (malignant hyperthermia, congenital myopathy, rhabdomyolysis)

New recommendation

European Journal of Human Genetics 2026· MayRead

Unmasking NF1 mosaicism: optical genome mapping identifies a novel t(15;17) translocation in melanocytes.

Mosaic neurofibromatosis type 1

Long-read sequencingNew mechanism

Journal of Medical Genetics 2026· MayRead

Metabolism / Epilepsy

Clinical Utility of Genetic Diagnosis in Drug-Resistant Epilepsy: Refining Classification and Guiding Therapy in an Egyptian Cohort.

Genetic drug-resistant epilepsy

Metabolism / EpilepsyTherapeutic implication

Clinical Genetics 2026· JunRead

Novel Haplotype-Based Noninvasive Prenatal Diagnosis for Recessive Single-Gene Disorders: A Proof-of-Concept Study.

Autosomal recessive single-gene disorders (non-invasive prenatal diagnosis)

Long-read WGSPrenatal application

Clinical Genetics 2026· JunRead

WGS / Diagnosis

Non-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy and Phenotypic Expansions.

Non-isolated Dandy-Walker malformation

WGS / DiagnosisPhenotypic expansion

Clinical Genetics 2026· JunRead

Autosomal dominantJournal

COCH-Related Hearing Loss in a French Cohort: Novel Variants and Genotype–Phenotype Correlations

Autosomal dominant non-syndromic sensorineural hearing loss (DFNA9)

Recurrent variantPhenotypic expansion

Genes 2026· MayRead

Autosomal dominantPubMed

Biliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings.

Myhre syndrome (multisystemic fibrosis)

Phenotypic expansionTherapeutic implication

American Journal of Medical Genetics A 2026· MayRead

Autosomal recessivePubMed

Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.

Hereditary sensory and autonomic neuropathy type 9 (HSAN9)

VUS reclassifiedLong-read sequencing

American Journal of Medical Genetics A 2026· MayRead

WGS / Diagnosis

Autosomal recessivePubMed

Elucidating the Genetic Landscape, Phenotypic Spectrum, and Pathogenic Mechanisms in a Turkish Cohort with Primary Microcephaly.

Primary hereditary microcephaly and syndromic primary microcephaly

WGS / DiagnosisNew gene

Clinical Genetics 2026· MayRead

Autosomal recessivePubMed

ESAM Loss of Function and Congenital Neurovascular Injury: Strengthening the Case for a Recognizable Clinical Phenotype.

ESAM congenital tight-junctionopathy

New mechanismFunctional SNV

Clinical Genetics 2026· JunRead

Autosomal dominantPubMed

Phenotypic Expansion of Autosomal Dominant SREBF1-Related Ichthyosis Follicularis, Atrichia, Photophobia: It Is in Fact the Same Condition as Hereditary Mucoepithelial Dysplasia.

SREBF1-syndromic epidermal differentiation disorder (SREBF1-sEDD)

Phenotypic expansionRecurrent variant

Clinical Genetics 2026· JunRead

Autosomal recessivePubMed

Biallelic STEAP3 Variant in Neonatal Hemophagocytic Lymphohistiocytosis.

STEAP3 biallelic neonatal hemophagocytic lymphohistiocytosis

Phenotypic expansionNew mechanism

Clinical Genetics 2026· JunRead

References and sources

KMT2D — Kabuki syndrome type 1. American Journal of Human Genetics 2026. PMID 42134323. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42134323/
TSC1 — Tuberous sclerosis complex. European Journal of Human Genetics 2026. PMID 42151584. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42151584/
COL1A1 — Osteogenesis imperfecta. European Journal of Human Genetics 2026. PMID 42120541. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42120541/
RAC1 — RAC1-related neurodevelopmental disorder. European Journal of Human Genetics 2026. PMID 42120539. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42120539/
RYR1 — RYR1-related disorders (malignant hyperthermia, congenital myopathy, rhabdomyolysis). European Journal of Human Genetics 2026. PMID 42120542. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42120542/
NF1 — Mosaic neurofibromatosis type 1. Journal of Medical Genetics 2026. PMID 42144273. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42144273/
Genetic drug-resistant epilepsy. Clinical Genetics 2026. PMID 41693309. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41693309/
Autosomal recessive single-gene disorders (non-invasive prenatal diagnosis). Clinical Genetics 2026. PMID 41681029. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41681029/
Non-isolated Dandy-Walker malformation. Clinical Genetics 2026. PMID 41736477. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41736477/
SMAD4 — Myhre syndrome (multisystemic fibrosis). American Journal of Medical Genetics A 2026. PMID 42135274. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42135274/
TECPR2 — Hereditary sensory and autonomic neuropathy type 9 (HSAN9). American Journal of Medical Genetics A 2026. PMID 42109093. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42109093/
Primary hereditary microcephaly and syndromic primary microcephaly. Clinical Genetics 2026. PMID 42141383. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42141383/
ESAM — ESAM congenital tight-junctionopathy. Clinical Genetics 2026. PMID 41525715. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/41525715/
SREBF1 — SREBF1-syndromic epidermal differentiation disorder (SREBF1-sEDD). Clinical Genetics 2026. PMID 41492963. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/41492963/
STEAP3 — STEAP3 biallelic neonatal hemophagocytic lymphohistiocytosis. Clinical Genetics 2026. PMID 41556408. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/41556408/
COCH — Autosomal dominant non-syndromic sensorineural hearing loss (DFNA9). Genes 2026. doi:10.3390/genes17050588. Score 6/10. https://www.mdpi.com/2073-4425/17/5/588