Constitutional genetics

Week of 22 September 2026

14 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►MYBPC3 — a deep-intronic variant predicted benign by SpliceAI explains 35 supposedly genotype-negative hypertrophic cardiomyopathies.
►GAD2 — new gene for developmental encephalopathy with early-onset seizures, confirmed by a concordant knockout mouse model.
►DMD — meta-analysis of AAV gene therapies: modest functional benefit, markedly greater at 4-5 years than at 6-7 years.
►Paternal germline — six of 127 fathers carried pathogenic sperm mosaicism, but 74% of the burden still stems from paternal age.
►FRMD7 — penetrance in female carriers rises from 30% to 50% depending on whether the variant is truncating or not.

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Autosomal dominantPubMed

Natural Missplicing Events Amplified by an Elusive Deep-Intronic MYBPC3 Variant Cause Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy

CardiologyDeep intronic variantRecurrent variant

Circulation 2026· SepRead

Autosomal recessivePubMed

Bi-allelic GAD2 variants cause a rare developmental encephalopathy with early-onset seizures.

Developmental encephalopathy with early-onset seizures

NeurodevelopmentNew geneFunctional SNV

Genet Med 2026· SepRead

Récessif lié à l'XPubMed

Safety and efficacy of AAV-based mini- and micro-dystrophin gene therapies in Duchenne muscular dystrophy: a systematic review and meta-analysis of clinical trials.

Duchenne muscular dystrophy

Therapeutic implication

J Med Genet 2026· SepRead

Autosomal dominantPubMed

ADNP-Related Helsmoortel-Van der Aa Syndrome: A Review of the Literature and Clinical Recommendations for Assessment and Monitoring.

Helsmoortel-Van der Aa syndrome

NeurodevelopmentNew recommendation

Am J Med Genet A 2026· SepRead

WGS / Diagnosis

Mutation timing, accumulation, and selection in the male germline shape inheritance risk for developmental disorders.

Developmental disorders caused by de novo mutations

WGS / DiagnosisNew mechanism

Cell Genom 2026· SepRead

Autosomal recessivePubMed

Biallelic RDH11 variants cause syndromic retinitis pigmentosa with early-onset cataracts and neurodevelopmental delay: a multicenter case series.

Syndromic retinitis pigmentosa with early-onset cataract

NeurodevelopmentRecurrent variantPhenotypic expansion

Eur J Hum Genet 2026· SepRead

Autosomal recessivePubMed

Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.

PGAP1 deficiency, a GPI-anchor-related neurodevelopmental disorder

NeurodevelopmentPhenotypic expansionFunctional SNV

Eur J Hum Genet 2026· SepRead

Autosomal recessive ou autosomal dominantPubMed

Zygosity-Dependent Phenotypic Spectrum of RELN-Related Disorders: 10 New Patients and Genotype-Phenotype Correlations Across 48 Kindreds.

Lissencephaly with cerebellar hypoplasia and focal epilepsies

NeurodevelopmentPhenotypic expansionVUS reclassified

Hum Mutat 2026· SepRead

Autosomal recessivePubMed

Genetic Spectrum of Cholestasis in Tunisia and Diagnostic Yield of Next-Generation Sequencing: Case Series of 70 Patients.

Genetic cholestasis in children

PrenatalRecurrent variantPrenatal application

Clin Genet 2026· SepRead

Neurodevelopment

Diagnosis Through Whole Genome Sequencing and Care Utilization in Children With Severe Illness.

Rare disease in severely ill children

NeurodevelopmentClinical pipeline

JAMA Netw Open 2026· SepRead

WGS / Diagnosis

Autosomal dominantPubMed

Precision Health Genetic Screening: Protocol and results categories for a clinical population genetic screening program.

Population genetic screening for CDC Tier 1 conditions

WGS / DiagnosisClinical pipelineVUS reclassified

Genet Med 2026· SepRead

Optical genome mapping identifies cryptic balanced chromosomal rearrangements in karyotypically normal couples with recurrent pregnancy loss or adverse pregnancy history.

Recurrent pregnancy loss and adverse pregnancy history

PrenatalClinical pipelinePrenatal application

Hum Mol Genet 2026· SepRead

Autosomal recessivePubMed

Phenotypic spectrum and quality of life in pediatric Bruck syndrome due to FKBP10 and PLOD2 variants: a 2-center United Arab Emirates experience.

Recurrent variantPhenotypic expansion

JBMR Plus 2026· AugRead

Nontruncating FRMD7 Variants Are More Penetrant than Truncating Variants in Heterozygous Female Carriers of Infantile Nystagmus.

X-linked infantile nystagmus

Penetrance updateRecurrent variant

Ophthalmol Sci 2026· AugRead

References and sources

MYBPC3 — Hypertrophic cardiomyopathy. Circulation 2026. PMID 42741831. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42741831/
GAD2 — Developmental encephalopathy with early-onset seizures. Genet Med 2026. PMID 42741920. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42741920/
DMD — Duchenne muscular dystrophy. J Med Genet 2026. PMID 42749483. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42749483/
ADNP — Helsmoortel-Van der Aa syndrome. Am J Med Genet A 2026. PMID 42753173. Score 7/10. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.70288?af=R
Developmental disorders caused by de novo mutations. Cell Genom 2026. PMID 42748923. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42748923/
RDH11 — Syndromic retinitis pigmentosa with early-onset cataract. Eur J Hum Genet 2026. PMID 42749779. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42749779/
PGAP1 — PGAP1 deficiency, a GPI-anchor-related neurodevelopmental disorder. Eur J Hum Genet 2026. PMID 42754667. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42754667/
RELN — Lissencephaly with cerebellar hypoplasia and focal epilepsies. Hum Mutat 2026. PMID 42761500. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42761500/
ABCB11 — Genetic cholestasis in children. Clin Genet 2026. PMID 42742065. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42742065/
Rare disease in severely ill children. JAMA Netw Open 2026. PMID 42752907. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42752907/
Population genetic screening for CDC Tier 1 conditions. Genet Med 2026. PMID 42762085. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42762085/
Recurrent pregnancy loss and adverse pregnancy history. Hum Mol Genet 2026. PMID 42762433. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42762433/
FKBP10 — Bruck syndrome. JBMR Plus 2026. PMID 42741659. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42741659/
FRMD7 — X-linked infantile nystagmus. Ophthalmol Sci 2026. PMID 42763576. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42763576/

15 September 2026