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In a recent study, a homozygous missense variant in TBC1D31 was identified in three siblings from a consanguineous family presenting with congenital anomalies of the kidney and urinary tract (CAKUT) (PMID:37468454). This report provides the first evidence linking TBC1D31 to CAKUT, thereby expanding the genetic spectrum of the disease.
The genetic findings indicate an autosomal recessive inheritance pattern. In this family, the three affected siblings, including a pair of monozygotic twins, demonstrate segregation of the TBC1D31 variant. The segregation of the variant within the family supports its role in the phenotype, with two additional affected relatives beyond the index case (PMID:37468454).
Detailed genetic evidence is provided by the identification of a single coding variant, c.187C>G (p.Gln63Glu), which was found in the affected individuals. The variant was discovered through whole‐exome sequencing and is consistent with autosomal recessive transmission, strongly supporting its pathogenic role in CAKUT (PMID:37468454).
The in‐silico analyses, including three‑dimensional protein modeling and molecular dynamics simulations, further support this association. These functional assessments predict that the c.187C>G (p.Gln63Glu) change disrupts normal protein structure and function, which is concordant with the clinical phenotype observed in the affected siblings (PMID:37468454).
Integration of both genetic and functional evidence provides a coherent narrative for the role of TBC1D31 in CAKUT. Although the findings are based on a single consanguineous family, the segregation data and supportive in‑silico functional evidence together yield moderate evidence for the gene‑disease association.
Key Take‑home: The identification of the homozygous c.187C>G (p.Gln63Glu) variant in TBC1D31 in affected siblings, supported by robust in‑silico modeling, underlines its clinical utility as a novel genetic marker for CAKUT.
Gene–Disease AssociationModerateThree affected siblings, including monozygotic twins, segregate the homozygous TBC1D31 variant with CAKUT, with supportive in‑silico structural modeling providing moderate evidence (PMID:37468454). Genetic EvidenceModerateA single homozygous missense variant, c.187C>G (p.Gln63Glu), was identified in 3 probands from a consanguineous family, consistent with autosomal recessive inheritance (PMID:37468454). Functional EvidenceModerateThree‑dimensional protein modeling and molecular dynamics simulations predict that the variant adversely affects TBC1D31 structure and function, supporting its pathogenicity in CAKUT (PMID:37468454). |