Week of 20 May 2026
Literature review — Constitutional genetics
16
curated articles
2
score ≥ 8/10
1
new genes
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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Articles of the week
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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 screeningDonnées de pénétrancePrenatal 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 screeningDonnées de pénétrancePrenatal 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