npj Genomic Medicine (Jul 2022)

Allelic overload and its clinical modifier effect in Bardet-Biedl syndrome

  • Irene Perea-Romero,
  • Carlos Solarat,
  • Fiona Blanco-Kelly,
  • Iker Sanchez-Navarro,
  • Brais Bea-Mascato,
  • Eduardo Martin-Salazar,
  • Isabel Lorda-Sanchez,
  • Saoud Tahsin Swafiri,
  • Almudena Avila-Fernandez,
  • Inmaculada Martin-Merida,
  • Maria Jose Trujillo-Tiebas,
  • Ester Carreño,
  • Belen Jimenez-Rolando,
  • Blanca Garcia-Sandoval,
  • Pablo Minguez,
  • Marta Corton,
  • Diana Valverde,
  • Carmen Ayuso

Journal volume & issue
Vol. 7, no. 1
pp. 1 – 7


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Abstract Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy characterized by extensive inter- and intra-familial variability, in which oligogenic interactions have been also reported. Our main goal is to elucidate the role of mutational load in the clinical variability of BBS. A cohort of 99 patients from 77 different families with biallelic pathogenic variants in a BBS-associated gene was retrospectively recruited. Human Phenotype Ontology terms were used in the annotation of clinical symptoms. The mutational load in 39 BBS-related genes was studied in index cases using different molecular and next-generation sequencing (NGS) approaches. Candidate allele combinations were analysed using the in silico tools ORVAL and DiGePred. After clinical annotation, 76 out of the 99 cases a priori fulfilled established criteria for diagnosis of BBS or BBS-like. BBS1 alleles, found in 42% of families, were the most represented in our cohort. An increased mutational load was excluded in 41% of the index cases (22/54). Oligogenic inheritance was suspected in 52% of the screened families (23/45), being 40 tested by means of NGS data and 5 only by traditional methods. Together, ORVAL and DiGePred platforms predicted an oligogenic effect in 44% of the triallelic families (10/23). Intrafamilial variable severity could be clinically confirmed in six of the families. Our findings show that the presence of more than two alleles in BBS-associated genes correlated in six families with a more severe phenotype and associated with specific findings, highlighting the role of the mutational load in the management of BBS cases.