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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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KMT2D
Autosomique dominantPubMedA next-generation episignature for Kabuki syndrome enables fine mapping of the impact of KMT2D variants to inform precision medicine.
Kabuki syndrome type 1
8
/10
NeurodevelopmentVUS reclassifiedLong-read sequencing
American Journal of Human Genetics 2026· MayRead
TSC1, TSC2
Autosomique dominantPubMedUncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening.
Tuberous sclerosis complex
8
/10
Newborn screeningPenetrance updatePrenatal application
European Journal of Human Genetics 2026· MayRead
COL1A1, COL1A2
Autosomique dominantPubMedReduced penetrance of COL1A1/2 pathogenic variants linked with osteogenesis imperfecta: analysis of a large population cohort.
Osteogenesis imperfecta
7
/10
Newborn screeningPenetrance updatePrenatal application
European Journal of Human Genetics 2026· MayRead
RAC1
Autosomique dominantPubMedDistinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1.
RAC1-related neurodevelopmental disorder
7
/10
NeurodevelopmentPhenotypic expansionFunctional SNV
European Journal of Human Genetics 2026· MayRead
RYR1
PubMedEMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders.
RYR1-related disorders (malignant hyperthermia, congenital myopathy, rhabdomyolysis)
6
/10
New recommendation
European Journal of Human Genetics 2026· MayRead
NF1
PubMedUnmasking NF1 mosaicism: optical genome mapping identifies a novel t(15;17) translocation in melanocytes.
Mosaic neurofibromatosis type 1
6
/10
Long-read sequencingNew mechanism
Journal of Medical Genetics 2026· MayRead
Metabolism / Epilepsy
PubMedClinical Utility of Genetic Diagnosis in Drug-Resistant Epilepsy: Refining Classification and Guiding Therapy in an Egyptian Cohort.
Genetic drug-resistant epilepsy
6
/10
Metabolism / EpilepsyTherapeutic implication
Clinical Genetics 2026· JunRead
Long-read WGS
PubMedNovel Haplotype-Based Noninvasive Prenatal Diagnosis for Recessive Single-Gene Disorders: A Proof-of-Concept Study.
Autosomal recessive single-gene disorders (non-invasive prenatal diagnosis)
6
/10
Long-read WGSPrenatal application
Clinical Genetics 2026· JunRead
WGS / Diagnosis
PubMedNon-Isolated Dandy-Walker Malformation: Exome Sequencing Efficacy and Phenotypic Expansions.
Non-isolated Dandy-Walker malformation
6
/10
WGS / DiagnosisPhenotypic expansion
Clinical Genetics 2026· JunRead
COCH
Autosomique dominantJournalCOCH-Related Hearing Loss in a French Cohort: Novel Variants and Genotype–Phenotype Correlations
Autosomal dominant non-syndromic sensorineural hearing loss (DFNA9)
6
/10
Recurrent variantPhenotypic expansion
Genes 2026· MayRead
SMAD4
Autosomique dominantPubMedBiliary Cirrhosis in Myhre Syndrome: The First Case Report of Liver Transplantation and a Review of Reported Hepatic Findings.
Myhre syndrome (multisystemic fibrosis)
5
/10
Phenotypic expansionTherapeutic implication
American Journal of Medical Genetics A 2026· MayRead
TECPR2
Autosomique récessifPubMedUnraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.
Hereditary sensory and autonomic neuropathy type 9 (HSAN9)
5
/10
VUS reclassifiedLong-read sequencing
American Journal of Medical Genetics A 2026· MayRead
WGS / Diagnosis
Autosomique récessifPubMedElucidating the Genetic Landscape, Phenotypic Spectrum, and Pathogenic Mechanisms in a Turkish Cohort with Primary Microcephaly.
Primary hereditary microcephaly and syndromic primary microcephaly
5
/10
WGS / DiagnosisNew gene
Clinical Genetics 2026· MayRead
ESAM
Autosomique récessifPubMedESAM Loss of Function and Congenital Neurovascular Injury: Strengthening the Case for a Recognizable Clinical Phenotype.
ESAM congenital tight-junctionopathy
5
/10
New mechanismFunctional SNV
Clinical Genetics 2026· JunRead
SREBF1
Autosomique dominantPubMedPhenotypic 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)
5
/10
Phenotypic expansionRecurrent variant
Clinical Genetics 2026· JunRead
STEAP3
Autosomique récessifPubMedBiallelic STEAP3 Variant in Neonatal Hemophagocytic Lymphohistiocytosis.
STEAP3 biallelic neonatal hemophagocytic lymphohistiocytosis
5
/10
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, TSC2 — Tuberous sclerosis complex. European Journal of Human Genetics 2026. PMID 42151584. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42151584/
- COL1A1, COL1A2 — 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