TUBGCP4 – Microcephaly and Chorioretinopathy 3

TUBGCP4-related microcephaly and chorioretinopathy 3 is a rare autosomal recessive neuro-ophthalmologic disorder characterized by prenatal-onset microcephaly, microphthalmia and punched-out chorioretinal lesions. Bi-allelic LoF or splice-altering variants in TUBGCP4 disrupt γ-tubulin ring complex (γ-TuRC) function, leading to defective microtubule nucleation and organization in neural and retinal progenitors.

Genetic evidence includes at least 6 unrelated probands with compound heterozygous or homozygous TUBGCP4 variants: 3 from functional studies (PMID:25817018) and a clinical case report (PMID:32270730), with additional single cases in 2022 and 2023. Variant spectrum is dominated by predicted null alleles: nonsense, frameshift and essential splice site changes, e.g., c.61A>T (p.Lys21Ter) (PMID:25817018).

Segregation analysis in one multiplex family confirmed compound heterozygosity with two affected siblings (1 additional relative segregating) and parental carrier status (PMID:25817018). This supports autosomal recessive inheritance with full penetrance for neuro-ophthalmic features.

Functional assays demonstrate that patient fibroblasts harboring TUBGCP4 variants have reduced γ-TuRC levels, altered microtubule nucleation and organization, abnormal nuclear morphology and aneuploidy. Zebrafish morphants phenocopy human microcephaly and chorioretinal dysplasia, confirming a loss-of-function mechanism (PMID:25817018).

Conflicting evidence arises from a 5-year-old with homozygous synonymous c.1746G>T (p.Leu582=) who presented with autism and eye anomalies but lacked microcephaly or chorioretinopathy, suggesting variable expressivity or incomplete penetrance (PMID:35418825).

Integration of genetic and experimental data yields a Strong gene–disease association: bi-allelic LoF/splice variants in TUBGCP4 cause disrupted γ-TuRC function, leading to neuro-ophthalmic pathology. Key take-home: molecular testing of TUBGCP4 should be considered in patients with congenital microcephaly and chorioretinopathy to guide diagnosis and genetic counseling.

References

• American Journal of Human Genetics • 2015 • Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy PMID:25817018
• Ophthalmic Genetics • 2020 • TUBGCP4 - associated microcephaly and chorioretinopathy PMID:32270730
• Molecular Syndromology • 2022 • Bi-Allelic c.1746G>T; p.Leu582= Variants in TUBGCP4 in a Boy with Autism: Clinical Data and Literature Review PMID:35418825
• Ophthalmic Genetics • 2023 • Microcephaly and chorioretinopathy associated with TUBGCP4: a case report and a review of the literature PMID:37038737

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