Constitutional genetics

Week of 3 November 2026

15 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►VPS25 — new gene for a lethal recessive neonatal encephalopathy: 5 families, mouse model and defective exosome secretion.
►PRKCZ — new gene for adult-onset retinitis pigmentosa: 13 patients from 10 families, a mechanism specific to the long retinal isoform.
►DDX41 — the hematologic malignancy predisposition gene causes, when biallelic, an early-onset retinal dystrophy (8 families, preprint).
►COL4A3 / COL4A4 — across two large genomic cohorts, truncating and NC1 missense variants do not carry the same pathogenicity depending on the gene.
►Pyruvate dehydrogenase deficiency — international consensus guidelines: 199 Delphi-agreed, GRADE-rated recommendations.

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Autosomal recessivePubMed

Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy

Lethal neonatal encephalopathy with severe hypotonia, brain anomalies and epilepsy

NeurodevelopmentNew geneFunctional SNV

Genome Med 2026· SepRead

Autosomal recessivePubMed

Bi-Allelic PRKCZ Loss-of-Function Variants and Adult-Onset Retinitis Pigmentosa

Adult-onset retinitis pigmentosa

New geneFunctional SNV

JAMA Ophthalmol 2026· OctRead

Autosomal recessivePubMed

Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

Leber congenital amaurosis and early-onset severe retinal dystrophy (LCA/EOSRD)

New geneFunctional SNV

medRxiv 2026· JanRead

COL4A3, COL4A4

Population-scale genomics reveals divergent pathogenicity of variant classes across paralogous collagen IV genes

Collagen IV nephropathies (hematuria, proteinuria, chronic kidney disease)

Am J Hum Genet 2026· NovRead

Metabolism / Epilepsy

Consensus Guidelines for Diagnosis and Management of Pyruvate Dehydrogenase Complex Deficiency

Pyruvate dehydrogenase complex deficiency (PDCD)

Metabolism / EpilepsyTherapeutic implication

J Inherit Metab Dis 2026· OctRead

Neurodevelopment

Diagnostic Yield and Clinical Actionability of Genetic Testing in Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis

Neurodevelopmental disorders (autism spectrum disorder, intellectual disability, global developmental delay)

Neurodevelopment

Int J Mol Sci 2026· OctRead

Genotype and phenotype analyses of 689 individuals with PCDH19-clustering epilepsy

PCDH19-clustering epilepsy (PCDH19-CE)

Neurodevelopment

Mol Psychiatry 2026· OctRead

Metabolism / Epilepsy

Germline Genetic Variants and Epilepsy Surgery Response: Individual Participant Pooled Analysis of 272 Patients

Germline genetic epilepsies treated with surgery

Metabolism / EpilepsyTherapeutic implication

Neurology 2026· NovRead

Autosomal dominantPubMed

Customized MUC1 Sequencing Enables Diagnosis of Autosomal Dominant Tubulointerstitial Kidney Disease and Unexplained CKD

MUC1-related autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1) and unexplained chronic kidney disease

WGS / Diagnosis

Kidney Int Rep 2026· SepRead

WGS / Diagnosis

Whole-Genome Sequencing in Diagnostics of Unsolved Cases of Inherited Retinal Diseases

Unsolved inherited retinal diseases

WGS / DiagnosisDeep intronic variant

Int J Mol Sci 2026· OctRead

Autosomal recessivePubMed

Biallelic loss-of-function PTPN6 variants lead to inflammatory lung disease and hemolytic anemia

Inborn error of immunity with severe inflammatory lung disease and hemolytic anemia

Phenotypic expansionFunctional SNV

J Exp Med 2026· OctRead

Genetic diagnostic yield of prenatal testing for fetal central nervous system abnormalities: a phenotype-driven study in a large single-center cohort

Fetal central nervous system abnormalities

PrenatalPrenatal application

Hum Genomics 2026· AugRead

Long-read genome sequencing resolves complex structural variants in exome-negative developmental and epileptic encephalopathy

Exome-negative developmental and epileptic encephalopathies

Long-read WGSLong-read sequencing

medRxiv 2026· OctRead

Autosomal recessivePubMed

PIH1D2 Loss-of-Function Directs Ciliary and Cell Cycle Defects Resulting in Left Isomerism With or Without Biliary Atresia

Left isomerism heterotaxy with or without biliary atresia

WGS / DiagnosisNew geneFunctional SNV

Liver Int 2026· OctRead

WGS / Diagnosis

Low Incidence of Cryptic Genetic Marrow Failure in Pediatric Severe Aplastic Anemia Following Negative Clinical Workup

Pediatric severe aplastic anemia and inherited bone marrow failure syndromes

WGS / Diagnosis

Blood 2026· OctRead

References and sources

VPS25 — Lethal neonatal encephalopathy with severe hypotonia, brain anomalies and epilepsy. Genome Med 2026. PMID 42934717. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/42934717/
PRKCZ — Adult-onset retinitis pigmentosa. JAMA Ophthalmol 2026. PMID 42955015. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42955015/
DDX41 — Leber congenital amaurosis and early-onset severe retinal dystrophy (LCA/EOSRD). medRxiv 2026. PMID 41646732. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/41646732/
COL4A3, COL4A4 — Collagen IV nephropathies (hematuria, proteinuria, chronic kidney disease). Am J Hum Genet 2026. PMID 42971206. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42971206/
Pyruvate dehydrogenase complex deficiency (PDCD). J Inherit Metab Dis 2026. PMID 42823914. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42823914/
Neurodevelopmental disorders (autism spectrum disorder, intellectual disability, global developmental delay). Int J Mol Sci 2026. PMID 42941883. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42941883/
PCDH19 — PCDH19-clustering epilepsy (PCDH19-CE). Mol Psychiatry 2026. PMID 42963370. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42963370/
Germline genetic epilepsies treated with surgery. Neurology 2026. PMID 42970749. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42970749/
MUC1 — MUC1-related autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1) and unexplained chronic kidney disease. Kidney Int Rep 2026. PMID 42964607. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42964607/
Unsolved inherited retinal diseases. Int J Mol Sci 2026. PMID 42941794. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42941794/
PTPN6 — Inborn error of immunity with severe inflammatory lung disease and hemolytic anemia. J Exp Med 2026. PMID 42841903. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42841903/
Fetal central nervous system abnormalities. Hum Genomics 2026. PMID 42958445. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42958445/
Exome-negative developmental and epileptic encephalopathies. medRxiv 2026. doi:10.64898/2026.10.26.26365902. Score 6/10. https://www.medrxiv.org/content/10.64898/2026.10.26.26365902v1
PIH1D2 — Left isomerism heterotaxy with or without biliary atresia. Liver Int 2026. PMID 42947407. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42947407/
Pediatric severe aplastic anemia and inherited bone marrow failure syndromes. Blood 2026. PMID 42949905. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42949905/

27 October 2026