A case report of an Iranian patient with Bardet-Biedl syndrome (BBS) identified two new mutations associated with the genetic condition. The findings were established using a large-scale gene sequencing approach known as next-generation sequencing.
The case report, “Identification of A Novel Compound Heterozygous Mutation in BBS12 in An Iranian Family with Bardet-Biedl Syndrome Using Targeted Next Generation Sequencing” was published in the Cell Journal.
BBS is a rare genetic condition with a variety of symptoms, including obesity, mental disabilities, kidney abnormalities, and polydactyly (extra fingers or toes). Mutations in a group of 19 identified genes account for more than 80% of the known BBS cases.
The syndrome is an autosomal recessive disorder, meaning that it requires a mutation of both gene alleles — one inherited from the mother and one from the father. Mutations of both alleles can be identical (homozygous) or different (heterozygous).
As a genetic condition, BBS is most common in populations with a high level of consanguinity. Also, the specific gene causing BBS may vary depending on region. For instance, mutations in genes BBS2, BBS4, BBS5, and BBS12 are most common in the Middle East and North Africa; mutations in genes BBS1 and BBS10 are most commonly found in North America and Europe.
Advances in genetic sequencing have made it easier and cheaper to identify new mutations. Next-generation sequencing is an example of a promising tool that allows researchers to analyze complete genomes on a large scale and find new genetic features related to diseases.
In the study, researchers used next-generation sequencing to screen BBS-related genes in an Iranian girl with BBS symptoms, in order to identify the mutations causing the condition.
The 13-year-old was admitted to the Noor Medical Genetic Clinic in Iran for truncal obesity and blindness. She showed additional BBS-related symptoms, including polydactyly on the four limbs and congenital heart disease. Her parents were closely related (consanguineous marriage), but both were healthy, as was her brother.
Researchers screened 13 common BBS-associated genes (BBS1 to BBS13), and identified 22 gene mutations in the girl. Among these, they found two previously unidentified genetic variations on each allele (maternal and paternal) of the BBS12 gene.
The protein that BBS12 gene encodes is part of a larger protein complex, and BBS12 is one of the main genes causing BBS. The two newly identified mutations were BBS12 56T>G (at position 56) and BBS12 1156C>T (at position 1,156).
Computer simulation of the mutations showed that BBS12 56T>G was predicted to have a damaging effect on the protein structure, while BBS12 1,156C>T could be either damaging or benign. Apart from these two mutations, none of the other identified mutations was predicted to have damaging effects.
The team then analyzed the BBS12 sequence of the patient’s close family. While her mother carried the mutation BBS12 56T>G, her father had the mutation BBS12 1,156C>T.
Overall, the results suggest “a new probable genetic mechanism other than the conventional autosomal recessive inheritance of BBS,” the researchers said, as the patient had two different mutations in each allele instead of the same mutation in both (which characterizes autosomal recessive disorders).
Because of the rarity of BBS, current studies (including the present one) have been limited to small sample sizes. Nonetheless, the team noted that the study provided important information in identifying a new mutation type in BBS.