Bardet-Biedl Syndrome Diagnosis in Heterozygous TMEM67 Mutation Carriers
A patient who is heterozygous for a TMEM67 gene mutation does NOT have Bardet-Biedl syndrome (BBS), as BBS requires biallelic pathogenic variants (two mutations) for disease manifestation due to its autosomal recessive inheritance pattern. 1, 2, 3
Genetic Basis of BBS
BBS is inherited in an autosomal recessive manner, meaning affected individuals must carry two pathogenic variants (either homozygous or compound heterozygous) in one of the BBS genes to manifest the disease 1, 3, 4
Heterozygous carriers (with only one mutation) are asymptomatic and do not develop BBS-related features 2
A comprehensive study of 96 heterozygous BBS mutation carriers demonstrated that they had no increased predisposition to metabolic disorders (obesity, diabetes, hypertension) or renal impairment compared to non-carrier family members 2
TMEM67 and BBS
TMEM67 is NOT listed among the established BBS genes (BBS1-BBS17) that account for 70-80% of clinically diagnosed BBS cases 3, 5
TMEM67 mutations are instead associated with other ciliopathies, particularly Meckel-Gruber syndrome and Joubert syndrome, which can have overlapping phenotypic features with BBS but are distinct genetic entities 1
Diagnostic Requirements for BBS
To diagnose BBS, patients must have:
Two pathogenic variants identified in a single BBS gene (BBS1, BBS2, BBS10, BBS12, or other established BBS genes) 4, 5
Clinical features meeting diagnostic criteria, including primary features such as rod-cone dystrophy, obesity, polydactyly, hypogonadism, cognitive impairment, and renal abnormalities 1, 3, 4
Molecular genetic testing using multigenic panels is the standard diagnostic approach, with systematic analysis of the 12-14 established BBS genes 5
Critical Pitfall to Avoid
Do not confuse heterozygous carrier status with disease manifestation. The extensive study by Beales et al. definitively showed that heterozygous inheritance of BBS mutations does not predispose individuals to any BBS-related features, with body mass index, hypertension, diabetes, and chronic kidney disease rates being similar between carriers and non-carriers 2. This patient requires evaluation for alternative diagnoses if they have ciliopathy-related symptoms.