Constitutional genetics

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Constitutional genetics

Week of 22 April 2026

14 articles

Geno'X Veille — genox-veille.fr

Key takeaways this week

►PLEKHA6 — new IHH gene (~1.3% of cases) with a novel mechanism via kisspeptin secretion; add to IHH/Kallmann panels without delay.
►NME5 — new ASS gene (male infertility): complete LOF + functional + successful ICSI package.
►Biallelic RNU4-2 — new recessive syndrome distinct from dominant ReNU, with characteristic imaging (enlarged perivascular spaces).
►ZFHX4 — new NDD gene via haploinsufficiency; include in first-line exome panels.
►MAP2K4 — new candidate gene for syndromic NDD with genitourinary malformations.
►LDB1 — genotype–phenotype correlation by variant location (N-term vs C-term), useful for interpretation.
►IRF2BPL c.2152del — 3rd case of a recurrent variant with reproducible severe NEDAMSS + West phenotype.

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Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes

Novel recessive NDD syndrome with white matter abnormalities (distinct from dominant ReNU — MIM#620851)

New mechanismPhenotypic expansion

Nature Genetics, 58:761-773 (2026)Read

AD (pénétrance variable)medRxiv

PLEKHA6 — nouveau gène associé à l'hypogonadisme hypogonadotrope idiopathique (IHH)

Idiopathic hypogonadotropic hypogonadism (IHH) — endocrinology / reproduction

New geneNew mechanism

medRxiv preprint· AprRead

Discovery of a Pathogenic NME5 Variant Underlying Acephalic Spermatozoa Syndrome

Male infertility — acephalic spermatozoa syndrome (ASS)

Clinical Genetics, 2026 Feb;109(2):368-373· AugRead

AD de novoPubMed

Loss of function of the zinc finger homeobox 4 gene, ZFHX4, underlies a neurodevelopmental disorder

Novel neurodevelopmental disorder (intellectual disability / global delay)

Am J Hum Genet / Genet Med, 2025Read

AD de novomedRxiv

De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms

NDD — genotype–phenotype correlation driven by variant location

NeurodevelopmentNew mechanism

medRxiv preprint· FebRead

AD de novomedRxiv

De novo MAP2K4 variants cause a novel syndromic neurodevelopmental disorder

Novel syndromic NDD + congenital malformations (mostly genitourinary) + epilepsy

Metabolism / EpilepsyNew gene

medRxiv preprint· DecRead

XL de novo (♀)PubMed

De Novo Heterozygous ZFX Frameshift Variant in a Female With an X-Linked Neurodevelopmental Disorder

X-linked NDD (ZFX syndrome) — female presentation

WGS / DiagnosisPhenotypic expansionRecurrent variant

American Journal of Medical Genetics A, 2026 Feb;200(2):521-530· OctRead

Identification and Functional Characterization of a Novel SEMA3A Exon Deletion Variant in Kallmann Syndrome

Kallmann syndrome — HH16 (MIM#614897)

Revue d'endocrinologie/génétique, 2026Read

AR (à confirmer)medRxiv

HIPK4 is a novel gene associated with teratozoospermia

Male infertility — teratozoospermia

medRxiv preprint· MarRead

Loss of ABCA4 from photoreceptor discs triggers changes in glial cell homeostasis

Stargardt disease — STGD1 (MIM#248200)

bioRxiv preprint· AprRead

AD de novoPubMed

Recurrent IRF2BPL c.2152del Variant in NEDAMSS: A Case Report and Comparative Analysis

NEDAMSS (MIM#618088) + West syndrome

Recurrent variantPhenotypic expansion

American Journal of Medical Genetics A, online 2026-03-11· MarRead

Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene

PLACK syndrome (MIM#616295) + severe dilated cardiomyopathy (phenotypic expansion)

CardiologyPhenotypic expansion

Revue de cardiogénétique, 2026Read

Susceptibilité GWASbioRxiv

Characterization of variants associated with Cerebral Small Vessel Disease identifies a functional SNV in Versican (VCAN)

Cerebral small vessel disease (CSVD)

bioRxiv preprint· AprRead

Rare missense variants in TGFBR2 and FLNA identified by whole-exome sequencing in syndromic genetic aortopathy

Syndromic aortopathy — overlap with Loeys–Dietz syndrome 2 (MIM#610168)

Phenotypic expansion

medRxiv preprint· MarRead

References and sources

NME5 — Male infertility — acephalic spermatozoa syndrome (ASS). Clinical Genetics, 2026 Feb;109(2):368-373. PMID 41499646. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/41499646/
IRF2BPL — NEDAMSS (MIM#618088) + West syndrome. American Journal of Medical Genetics A, online 2026-03-11. PMID 41813602. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41813602/
ZFX — X-linked NDD (ZFX syndrome) — female presentation. American Journal of Medical Genetics A, 2026 Feb;200(2):521-530. PMID 41074764. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/41074764/
RNU4-2 — Novel recessive NDD syndrome with white matter abnormalities (distinct from dominant ReNU — MIM#620851). Nature Genetics, 58:761-773 (2026). PMID 41951959. Score 10/10. https://pubmed.ncbi.nlm.nih.gov/41951959/
CAST — PLACK syndrome (MIM#616295) + severe dilated cardiomyopathy (phenotypic expansion). Revue de cardiogénétique, 2026. PMID 41300744. Score 6/10. https://pubmed.ncbi.nlm.nih.gov/41300744/
SEMA3A — Kallmann syndrome — HH16 (MIM#614897). Revue d'endocrinologie/génétique, 2026. PMID 41532366. Score 7/10. https://pubmed.ncbi.nlm.nih.gov/41532366/
ZFHX4 — Novel neurodevelopmental disorder (intellectual disability / global delay). Am J Hum Genet / Genet Med, 2025. PMID 40367947. Score 9/10. https://pubmed.ncbi.nlm.nih.gov/40367947/
LDB1 — NDD — genotype–phenotype correlation driven by variant location. medRxiv preprint. doi:10.64898/2026.02.26.26347174. Score 8/10. https://www.medrxiv.org/content/10.64898/2026.02.26.26347174v1.article-info
MAP2K4 — Novel syndromic NDD + congenital malformations (mostly genitourinary) + epilepsy. medRxiv preprint. doi:10.64898/2025.12.23.25342932. Score 8/10. https://www.medrxiv.org/content/10.64898/2025.12.23.25342932v1.full.pdf
PLEKHA6 — Idiopathic hypogonadotropic hypogonadism (IHH) — endocrinology / reproduction. medRxiv preprint. doi:10.64898/2026.04.10.26349358. Score 10/10. https://www.medrxiv.org/content/10.64898/2026.04.10.26349358v1.full.pdf
HIPK4 — Male infertility — teratozoospermia. medRxiv preprint. doi:10.64898/2026.03.04.26346694. Score 7/10. https://www.medrxiv.org/content/10.64898/2026.03.04.26346694v1.full.pdf
TGFBR2 — Syndromic aortopathy — overlap with Loeys–Dietz syndrome 2 (MIM#610168). medRxiv preprint. doi:10.64898/2026.03.30.26349510. Score 5/10. https://www.medrxiv.org/content/10.64898/2026.03.30.26349510v1.full.pdf
ABCA4 — Stargardt disease — STGD1 (MIM#248200). bioRxiv preprint. doi:10.64898/2026.04.13.718110. Score 7/10. https://www.biorxiv.org/content/10.64898/2026.04.13.718110v1
VCAN — Cerebral small vessel disease (CSVD). bioRxiv preprint. doi:10.64898/2026.03.16.712010. Score 6/10. https://www.biorxiv.org/content/10.64898/2026.03.16.712010v2