Bardet-Biedl syndrome due to a pathogenic mutation on CEP290 and an unreported TTC8 variant

Abstract

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive or triallelic ciliopathy disorder characterized by obesity, male hypogonadism, renal impairment, polydactyly, and intellectual disability. We present a case report of an African-American male with excessive weight gain and prediabetes who was referred to Genetics at 2½ years of age. Physical exam findings included obesity, macrocephaly, bilateral macrotia, brachydactyly, and small genitalia. Gene sequencing identified two mutations highly suggestive of BBS: a heterozygous variant in the CEP290 gene (c.4393 C>T) and a heterozygous variant in the TTC8 gene (c.1021 C>T). Twenty-one genes have been associated with the 21 types of BBS to date, all demonstrating variable expressivity and incomplete penetrance. There is no cure for BBS, and current management focuses on preventing and treating symptoms. CEP290 mutations are associated with BBS type 14, and only 1% of affected individuals carry a mutation on this gene. TTC8 mutations are associated with BBS type 8, and its gene frequency is also 1% in individuals with BBS. The TTC8 variant found in our propositus (p.Arg341Trp) has not been previously reported in the Human Gene Mutation Database. In this variant, tryptophan replaces the normal arginine at position 341 of the TTC8 protein. To our knowledge, this is the first report linking this specific TTC8 variant with BBS. Keywords: Bardet-Biedl Syndrome, Ciliopathy disorder, Childhood obesity, Genetic obesity, CEP290, TTC8