Constitutional genetics

Week of 15 September 2026

11 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►SNORD118 — spatial proteomics on patient tissue nominates the VEGF pathway, and axitinib yields a response sustained beyond 35 months in leukoencephalopathy with calcifications and cysts.
►CYP21A2 — long-read sequencing unmasks "2+0" carriers, false negatives of standard techniques, and separates chimera subtypes in 21-hydroxylase deficiency.
►Undiagnosed disease — a 22.1% diagnostic rate across 1,713 UDN participants, with reanalysis of already generated sequencing data as the leading driver.
►CPLANE1 — an Alu element insertion invisible to short-read genome sequencing completes a recessive genotype and reclassifies a variant of uncertain significance as likely pathogenic.
►Molecular autopsy — 19% pathogenic variant detection after sudden death in the young (66 studies, 4,452 cases), 76% of them in ACMG Secondary Findings genes.

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Autosomal recessivePubMed

Proteomic-guided targeted treatment of leukoencephalopathy with calcification and cysts.

Leukoencephalopathy with calcifications and cysts (LCC)

Therapeutic implicationNew mechanism

Brain 2026· SepRead

WGS / Diagnosis

Arriving at a diagnosis: Effective strategies used by the Undiagnosed Diseases Network.

Undiagnosed rare disease

WGS / Diagnosis

Genet Med 2026· SepRead

Autosomal recessivePubMed

Long-read sequencing resolves complex CYP21A2 variants and identifies 2+0 carriers in 21-hydroxylase deficiency.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Long-read WGSLong-read sequencing

J Mol Diagn 2026· SepRead

Autosomal recessivePubMed

Unraveling the Clinical Spectrum of DNASE1L3 Deficiency: Insights from Case Series and Systematic Literature Review.

DNASE1L3 deficiency — monogenic lupus and vasculitis

Phenotypic expansion

Curr Rheumatol Rep 2026· SepRead

Detection rate of pathogenic variants by postmortem genetic testing for sudden cardiac death among children and young adults: systematic review and meta-analysis.

Sudden cardiac death in children and young adults

Genet Med 2026· SepRead

Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.

Unexplained sudden childhood death — concealed cardiomyopathy

Eur J Hum Genet 2026· SepRead

Identification of rare maternal copy number variants by genome-wide analysis of noninvasive prenatal screening data in 113,017 pregnant women.

Maternal copy number variants detected through noninvasive prenatal screening

PrenatalPrenatal application

Ann Med 2026· SepRead

Integrative analysis reveals regulatory effects of tandem repeat expansions in tetralogy of Fallot.

Tetralogy of Fallot — congenital heart disease

Long-read WGSRepeat expansionLong-read sequencing

medRxiv 2026· SepRead

Autosomal dominantPubMed

Pathogenicity of NUSAP1 Variants Is Defined by NMD-Escape: Evidence From Two Novel Cases and Systematic Population-Based Variant Analysis.

Developmental and epileptic encephalopathy with congenital microcephaly

NeurodevelopmentFunctional SNV

Clin Genet 2026· SepRead

Autosomal dominantmedRxiv

Thoracic Aortic Disease in Genetic Syndromes Beyond Established Aortopathy Genes

Thoracic aortic aneurysm and dissection in genetic syndromes

CardiologyPhenotypic expansion

medRxiv 2026· SepRead

Autosomal recessivePubMed

Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.

Orofaciodigital syndrome type VI

Long-read WGSLong-read sequencingVUS reclassified

Eur J Hum Genet 2026· SepRead

References and sources

SNORD118 — Leukoencephalopathy with calcifications and cysts (LCC). Brain 2026. PMID 42725622. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42725622/
CYP21A2 — Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Mol Diagn 2026. PMID 42727689. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42727689/
Undiagnosed rare disease. Genet Med 2026. PMID 42720004. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42720004/
DNASE1L3 — DNASE1L3 deficiency — monogenic lupus and vasculitis. Curr Rheumatol Rep 2026. PMID 42726335. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42726335/
NUSAP1 — Developmental and epileptic encephalopathy with congenital microcephaly. Clin Genet 2026. PMID 42706591. Score 6/10. https://onlinelibrary.wiley.com/doi/10.1111/cge.70244?af=R
Sudden cardiac death in children and young adults. Genet Med 2026. PMID 42708325. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42708325/
Unexplained sudden childhood death — concealed cardiomyopathy. Eur J Hum Genet 2026. PMID 42728322. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42728322/
Thoracic aortic aneurysm and dissection in genetic syndromes. medRxiv 2026. doi:10.64898/2026.09.04.26362279. Score 6/10. https://www.medrxiv.org/content/10.64898/2026.09.04.26362279v1
Maternal copy number variants detected through noninvasive prenatal screening. Ann Med 2026. PMID 42714190. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42714190/
Tetralogy of Fallot — congenital heart disease. medRxiv 2026. doi:10.64898/2026.09.08.26362566. Score 7/10. https://www.medrxiv.org/content/10.64898/2026.09.08.26362566v1
CPLANE1 — Orofaciodigital syndrome type VI. Eur J Hum Genet 2026. PMID 42732008. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42732008/

8 September 2026