Genetic and clinical characterization of Pakistani families with Bardet-Biedl syndrome extends the genetic and phenotypic spectrum

Abstract

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder that is both genetically and clinically heterogeneous. To date 19 genes have been associated with BBS, which encode proteins active at the primary cilium, an antenna-like organelle that acts as the cell’s signaling hub. In the current study, a combination of mutation screening, targeted sequencing of ciliopathy genes associated with BBS, and whole-exome sequencing was used for the genetic characterization of five families including four with classic BBS symptoms and one BBS-like syndrome. This resulted in the identification of novel mutations in BBS genes ARL6 and BBS5, and recurrent mutations in BBS9 and CEP164. In the case of CEP164, this is the first report of two siblings with a BBS-like syndrome with mutations in this gene. Mutations in this gene were previously associated with nephronophthisis 15, thus the current results expand the CEP164-associated phenotypic spectrum. The clinical and genetic spectrum of BBS and BBS-like phenotypes is not fully defined in Pakistan. Therefore, genetic studies are needed to gain insights into genotype-phenotype correlations, which will in turn improve the clinician’s ability to make an early and accurate diagnosis, and facilitate genetic counseling, leading to directly benefiting families with affected individuals.

Embryonic and foetal expression patterns of the ciliopathy geneCEP164

“…It is also well established that CEP164 is present at the basal body of retinal pigment epithelial cells, clarifying the results from our study [1, 2, 15, 17, 23]. It can be hypothesised that with abnormal functioning/loss of CEP164, there could be atypical outer segment formation, which could lead to the accumulation of phototransduction proteins that could trigger cell loss, leading to a retinal degeneration phenotype, as seen in some CEP164 NPHP-RC patients [1, 9, 44].…”

“…Intellectual disability and developmental delay can also be present, which is demonstrated throughout the spectrum of NPHP-RC. Additionally, BBS patients are often diagnosed with hypogonadism and/or obesity [9]. Severe NPHP-RC phenotypes, including Jeune syndrome and Meckel Gruber syndrome, can also present with skeletal dysplasia, and lethal occipital encephalocele.…”

“…Severe NPHP-RC phenotypes, including Jeune syndrome and Meckel Gruber syndrome, can also present with skeletal dysplasia, and lethal occipital encephalocele. Consistent with ciliopathy syndromes, polydactyly, liver fibrosis, facial dysmorphism, cardiac abnormalities, hearing loss and type 2 diabetes can present as secondary symptoms [9-11]. Although some disease management therapies are available, notably, there is no cure for NPHP-RC.…”

“…There are at least 25 NPHP-RC causative genes currently identified [12], accounting for a molecular genetic diagnosis in around 60% of NPHP-RC patients. Mutations in CEP164 , also known as NPHP15 , have been identified as a cause of NPHP-RC [1, 9]. These patients have a largely heterogenous clinical presentation.…”

“…The majority suffer with NPHP and a retinal phenotype, which is some patients cause blindness prior to two years of age. One patient was diagnosed with JBTS, and two others have BBS-like manifestations with an absence of renal problems [1, 9]. It has been proposed that homozygous truncating mutations of CEP164 , cause a severe JBTS phenotype, whereas hypomorphic mutations may cause a less severe phenotype [1].…”