Clinical and Genetic Characterization of a Russian Family with Bardet-Biedl Syndrome Carrying a Previously Undescribed Missense Variant and a Recurrent Pathogenic Frameshift Variant in BBS7 Gene.

Background/

Objectives

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy caused by variants in genes encoding components of the BBSome complex. Interpretation of rare variants in the BBS7 gene remains challenging, particularly for variants of uncertain significance. This study aimed to provide clinical and molecular genetic characterization of two siblings with a BBS phenotype harboring compound heterozygous variants in BBS7, including a previously undescribed missense variant.

Methods

Two siblings (aged 11 and 8 years) presenting with obesity, postaxial polydactyly, retinal dystrophy, and cystic renal dysplasia were clinically evaluated. Whole-exome sequencing was performed in the proband, followed by segregation analysis within the family. Variant classification was conducted according to ACMG/AMP guidelines, integrating allele frequency data, in silico predictions, segregation evidence, and structural modeling.

Results

Two heterozygous variants in the BBS7 gene (NM_176824.3) were identified in trans: a previously reported pathogenic frameshift variant, c.1967_1968delinsC, p.(Leu656ProfsTer18), and a missense variant, c.454T>C, p.(Cys152Arg), which, to the best of our knowledge, has not been previously reported in patients with Bardet-Biedl syndrome. The variant was extremely rare in population databases. Structural analysis suggested steric and electrostatic disruptions, including loss of a disulfide bond. Based on ACMG/AMP criteria, the variant was classified as likely pathogenic.

Conclusions

This case supports the likely pathogenic classification of the c.454T>C, p.(Cys152Arg) variant. The findings highlight the importance of integrating clinical, genetic, and structural data for the interpretation of rare variants in BBS-associated genes.