A Genotype–Phenotype Analysis of the Bardet–Biedl Syndrome in Puerto Rico

Abstract

Background: Bardet-Biedl syndrome is a complex heterogeneous ciliopathy caused by genetic mutations. Although establishing genotype-phenotype correlations has been challenging, some regional variations have been previously reported. Due to its relative geographic isolation, Puerto Rico has a greater prevalence of Bardet-Biedl syndrome than do other regions. We sought to characterize the most frequent genotypic variations in a local cohort of Bardet-Biedl syndrome patients and report any genotypic-phenotypic trends. Methods: Twenty-seven patients from an ophthalmology clinic in Puerto Rico with genetically confirmed Bardet-Biedl syndrome took a questionnaire inquiring about their most common symptoms. Ophthalmological information was obtained from patient records. The frequencies of the genotypic variations and symptoms were calculated. Results: In the study population, BBS1 was the most prevalent mutated gene, followed by BBS7. In the BBS1 group, we found homozygotes for c.1169T>G (p.Met390Arg) and c.1645G>T (p. Glu549*), and compound heterozygotes for c.1169T>G (p.Met390Arg) and c.1645G>T (p. Glu549*), with one patient having c.1645G>T (p.Glu549*) and c.432+1G>A (splice donor). All the BBS7 patients were homozygous for c.632C>T (p.Thr211Ile). Compared to BBS7, we found that BBS1 patients generally had a milder ocular and systemic phenotype. However, when analyzing different BBS1 variants, patients with mutations in c.1645G>T (p.Glu549*), both compound heterozygous and homozygous, had more severe systemic phenotypes, overall. Conclusion:Our study was the first detailed genotype-phenotype analysis of the Bardet-Biedl syndrome in Puerto Rico. Genetic mutations in BBS1 and BBS7 seem to be the most common culprits behind Bardet-Biedl syndrome in this population. Although patients diagnosed with BBS1 are likely to display milder systemic features, this was not the case with our BBS1 patients having the c.1645G>T (p.Glu549*) mutation. Further studies should focus on the c.1645G>T (p.Glu549*) mutation's impact on the BBS1 gene and protein product.

Review of the phenotypes and genotypes of Bardet-Biedl syndrome from China

“…Homozygous variants were noted in 10 patients (50.00%) and 10 (50.00%) compound heterozygous variants were noted in our series. Unlike a report from the United States ( Guardiola et al, 2021 ), which reported hot spot variants in BBS1 and BBS7 , at least 11 variants of BBS7 were reported in this series. The most common variant was the c.1002delT (p. Asn335Ilefs*47) variant, which was found in 7 patients (36.84%) from 5 families, including 2 homozygotes.…”

“…Except for one case without detailed data of variant, 19 BBS2 patients from 12 families were reported ( Xing et al, 2014 ; Chen et al, 2017 ; Li et al, 2017 ; Ding et al, 2018 ; Dan et al, 2020 ; Huang et al, 2021 ; Meng et al, 2021 ; Tang et al, 2022 ; Tao et al, 2022 ; Wei et al, 2022 ), including 12 (63.16%) compound heterozygous variants and 7 (36.84%) homozygous variants. Unlike report from the United States ( Guardiola et al, 2021 ), which reported hot spot variants in BBS1 and BBS7 , a total of 15 variants were reported in our series. The most common was the c.534+1G>T splicing variant in 9 patients (47.37%) from 5 families, including 2 homozygotes.…”

“…These were followed by BBS12 (8, 8.99%), BBS1 (6, 6.74%), BBS5 (5, 5.62%), BBS6/ MKKS (5, 5.62%), BBS9/PTHB1 (5, 5.62%), and BBS4 (4, 4.49%), as shown in Table 2 and Figure 1 . The proportions of BBS2 , BBS4 , BBS7 , and BBS9/PTHB1 were higher while the proportion of BBS1 was lower in our Chinese series than those in most reports outside China ( Moore et al, 2005 ; Forsythe and Beales, 2013 ; Mujahid et al, 2018 ; Guardiola et al, 2021 ). Moreover, the affected proteins of 62 patients (69.66%) were involved in the assembly of the BBSome complex while 23 (25.84%) were involved in the chaperone-like protein complexes.…”

“…This difference may imply the different genotype prominence in different geographic areas. This may also be associated with the fact that poor clinical diagnosis as BBS1 patients tend to have a milder pattern of disease ( Niederlova et al, 2019 ; Guardiola et al, 2021 ). The analysis for the relationship between genotype and phenotype is difficult, as this rare disease.…”

“…It is characterized by retinitis pigmentosa, obesity, renal abnormalities, polydactyly, mental retardation, and hypogonadism. Other symptoms including ophthalmic diseases (e.g., astigmatism, strabismus, cataracts), hearing impairment, craniofacial congenital anomalies, hypoplastic teeth, toe deformity, short stature, asthma, neurological impairment (e.g., ataxia, hyperspasmia, olfactory abnormalities, behavioral and mental disorders, and poor coordination), digestive system abnormalities (e.g., intestinal atresia, imperforate anus, congenital megacolon, liver fibrillation), metabolic abnormalities (e.g., insulin resistance, hyperglycemia, dyslipidemia, hypothyroidism, hypertension), and cardiovascular abnormalities, have also been reported ( Mujahid et al, 2018 ; Tsang et al, 2018 ; Guardiola et al, 2021 ; Zhong et al, 2023 ).…”