Constitutional genetics

Week of 29 September 2026

17 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►BRSK1 — second series after Epilepsia 2025 (a first case then nine through GeneMatcher): neurodevelopmental disorder with or without epilepsy, and three missense alleles that only partially rescue the Drosophila null mutant.
►CNV detection — exome/genome sequencing matches chromosomal microarray (concordance above 99% across more than 9,000 cases), with microarray adding at most 1% further detections after sequencing.
►Prenatal exome — 31.6% diagnostic yield (87/275) in a prospective Australian trio cohort, with 4.4% variants of uncertain significance.
►Non-diagnostic exomes — 40% of 192 participants at one UDN site obtain a diagnosis, and 72% of genetic diagnoses could have been made with the initial exome.
►Genomic newborn screening — four studies (over 10,800 newborns): 1.6 to 3.7% screen-positive, led by G6PD, but results hard to compare for lack of harmonisation.

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BMPR2

Autosomal dominantPubMed

⭐ À la une

A rare recurring gain-of-function variant in BMPR2 causes neurodevelopmental phenotypes in humans and flies.

Neurodevelopmental disorder with autism spectrum disorder and global developmental delay

NeurodevelopmentRecurrent variantPhenotypic expansion

Am J Hum Genet 2026· SepRead

BRSK1

Autosomal dominantPubMed

Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy.

Neurodevelopmental disorder with or without epilepsy

NeurodevelopmentFunctional SNVRecurrent variant

Am J Hum Genet 2026· SepRead

THOC2, THOC6, THOC7, ALYREF

PubMed

Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum.

Neurodevelopmental disability spectrum linked to TREX complex subunits

NeurodevelopmentRecurrent variantFunctional SNV

Genet Med 2026· SepRead

WGS / Diagnosis

PubMed

Copy Number Variant Detection by Exome/Genome Sequencing Versus Chromosomal Microarray: A Comparative Study of Over 9,000 Clinical Cases.

Copy number variant detection in clinical genetic diagnosis

WGS / DiagnosisClinical pipelineDiagnostic yield

Genet Med 2026· SepRead

Prenatal

PubMed

The Australian PreGen Study: Results From Prospective Prenatal Exome Sequencing in 275 Pregnancies.

Fetal structural anomalies investigated by prenatal exome sequencing

PrenatalPrenatal applicationDiagnostic yield

Prenat Diagn 2026· SepRead

WGS / Diagnosis

PubMed

Whole-genome sequencing characterizes monogenic and polygenic contributions to structural kidney and urinary tract malformations.

Congenital anomalies of the kidney and urinary tract (CAKUT)

WGS / DiagnosisDiagnostic yield

Kidney Int 2026· SepRead

WGS / Diagnosis

PubMed

Diagnostic Yield of Genetic Testing in Cerebral Palsy: A Systematic Review and Meta-Analysis.

Cerebral palsy

WGS / DiagnosisDiagnostic yield

JAMA Pediatr 2026· SepRead

PTPN11, HRAS, SOS1

PubMed

Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

Solid tumours in RASopathies (Noonan, Costello and cardiofaciocutaneous syndromes)

Penetrance update

J Med Genet 2026· SepRead

WGS / Diagnosis

PubMed

Not the end of the road: Achieving diagnoses following non-diagnostic exome sequencing: experiences at a clinical site of the Undiagnosed Diseases Network.

Diseases undiagnosed after exome or genome sequencing

WGS / DiagnosisGenomic reanalysisDiagnostic yield

Genet Med 2026· SepRead

PURA

PubMed

5q31 duplications encompassing PURA are associated with a neurodevelopmental disorder.

Neurodevelopmental disorder associated with 5q31 duplications encompassing PURA

NeurodevelopmentPhenotypic expansionFunctional validation

Eur J Hum Genet 2026· SepRead

WGS / Diagnosis

Autosomal recessivebioRxiv

In vitro pathogenicity evaluation of deep intronic variants for recessive genetic retinal diseases

Recessive inherited retinal diseases and deep intronic variants

WGS / DiagnosisDeep intronic variantFunctional SNV

bioRxiv 2026· SepRead

Long-read WGS

medRxiv

A stepwise short- and long-read whole genome sequencing strategy resolves previous genetically unresolved inherited retinal disease cases

Inherited retinal disease unresolved after short-read WGS

Long-read WGSGenomic reanalysisDiagnostic yield

medRxiv 2026· SepRead

Prenatal

PubMed

Diagnostic Yield of Sequencing in Prenatal Agenesis of the Corpus Callosum in a Well-Phenotyped International Cohort.

Prenatally diagnosed agenesis of the corpus callosum

PrenatalPrenatal applicationDiagnostic yield

Prenat Diagn 2026· SepRead

WGS / Diagnosis

PubMed

Genetic data sharing by clinical laboratories in Canada: A position statement by the Canadian College of Medical Geneticists.

Genetic data sharing by Canadian clinical laboratories

WGS / DiagnosisNew recommendation

Am J Hum Genet 2026· SepRead

Newborn screening

PubMed

International experiences of genomic newborn screening: Lessons from over 10,800 newborns.

Genomic newborn screening for rare diseases

Newborn screeningClinical pipeline

Am J Hum Genet 2026· SepRead

KAT6B

Autosomal dominantPubMed

Clinical and Molecular Delineation of KAT6B-Related Disorders: Novel Variants and Refined Genotype-Phenotype Correlations.

Phenotypic expansionDiagnostic RNA-seq

Hum Mutat 2026· SepRead

DAW1

Autosomal recessivePubMed

Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.

Heterotaxy with complex congenital heart disease, without primary ciliary dyskinesia

CardiologyFunctional SNVVUS reclassified

Eur J Hum Genet 2026· SepRead

References and sources

BMPR2 — Neurodevelopmental disorder with autism spectrum disorder and global developmental delay. Am J Hum Genet 2026. PMID 42767215. Score 8/10. https://pubmed.ncbi.nlm.nih.gov/42767215/
BRSK1 — Neurodevelopmental disorder with or without epilepsy. Am J Hum Genet 2026. PMID 42805187. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42805187/
THOC2, THOC6, THOC7, ALYREF — Neurodevelopmental disability spectrum linked to TREX complex subunits. Genet Med 2026. PMID 42781784. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42781784/
Copy number variant detection in clinical genetic diagnosis. Genet Med 2026. PMID 42765364. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42765364/
Fetal structural anomalies investigated by prenatal exome sequencing. Prenat Diagn 2026. PMID 42784838. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42784838/
Congenital anomalies of the kidney and urinary tract (CAKUT). Kidney Int 2026. PMID 42767608. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42767608/
Cerebral palsy. JAMA Pediatr 2026. PMID 42804221. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42804221/
PTPN11, HRAS, SOS1 — Solid tumours in RASopathies (Noonan, Costello and cardiofaciocutaneous syndromes). J Med Genet 2026. PMID 42716727. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42716727/
Diseases undiagnosed after exome or genome sequencing. Genet Med 2026. PMID 42803155. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42803155/
PURA — Neurodevelopmental disorder associated with 5q31 duplications encompassing PURA. Eur J Hum Genet 2026. PMID 42768094. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/42768094/
Recessive inherited retinal diseases and deep intronic variants. bioRxiv 2026. doi:10.64898/2026.09.18.752412. Score 6/10. https://www.biorxiv.org/content/10.64898/2026.09.18.752412v1
Inherited retinal disease unresolved after short-read WGS. medRxiv 2026. doi:10.64898/2026.09.23.26363559. Score 6/10. https://www.medrxiv.org/content/10.64898/2026.09.23.26363559v0
Prenatally diagnosed agenesis of the corpus callosum. Prenat Diagn 2026. PMID 42791457. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42791457/
Genetic data sharing by Canadian clinical laboratories. Am J Hum Genet 2026. PMID 42772292. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/42772292/
Genomic newborn screening for rare diseases. Am J Hum Genet 2026. PMID 42767216. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42767216/
KAT6B — KAT6B-related disorders (genitopatellar and Say-Barber-Biesecker-Young-Simpson syndromes). Hum Mutat 2026. PMID 42787795. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42787795/
DAW1 — Heterotaxy with complex congenital heart disease, without primary ciliary dyskinesia. Eur J Hum Genet 2026. PMID 42773161. Score 5/10. https://pubmed.ncbi.nlm.nih.gov/42773161/

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22 September 2026