In this study, an intrauterine ultrasound was conducted to determine the phenotype of a fetus with bilateral-kidney enlargement, enhanced echo, polycystic kidney, and an amniotic fluid index of 2.9 cm (a low level at 24+2 weeks of gestation). We first used traditional karyotype analysis and an SNP-array to conduct genetic testing on the fetus, but no abnormalities were detected. Further genetic testing of the fetus was then performed using WES. This revealed homozygous variation of c.1177C>T (NM_024649.4, p.Arg393*) in exon 12 of the fetus’s BBS1 gene. Sanger sequencing also showed that there were heterozygous mutations in the same positions on genes in the parents of the fetus. This is consistent with the autosomal recessive inheritance of BBS.
BBS1 (OMIM:209901) is located on chromosome 11q13 and is also known as BBS2L2. At present, 94 pathogenic variants of BBS1 have been reported by the HGMD. Mutation of the BBS1 gene is the most common cause of BBS, and is responsible for 25% of all BBS incidences. The exact type of mutation varies among ethnic groups, with the most common BBS1 variant (p.M390R) accounting for about 80% of all BBS1 mutations in the European population [23, 24]. Mykytyn et al.  conducted genetic screening on 129 patients with BBS and found that 30% of them possessed at least one M390R mutation. BBS proteins encoded by different BBS genes are known to function throughout the formation of the BBS complex, including the BBSome, which consists of seven BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9) [26–29]. Mutation of the BBS1 gene results in abnormal function of the BBSome, which, in turn, affects the function of microcilia and various systems in the body . The homozygous variation of c.1177C>T (NM_024649.4, p.arg393*) in exon 12 of the BBS1 gene has not been reported in the Chinese population.
Most BBS1 variants include missense, deletion/insertion, and splicing mutations, and have been reported to produce typical BBS phenotypes [31–34]. According to recent studies, 90% of BBS patients have retinal degeneration in their clinical phenotypes of BBS patients , 90% have abnormal renal development and function , and 72-92% are obese . Additionally, 63-81% have polydactyly/deformity , and more than half have intellectual disability and/or gonadal dysplasia . Fetuses in this study had a nonsense variant of BBS1 with biallelic loss of function. Renal abnormalities in the sonographic phenotype of the fetus in our own study are consistent with previously reported clinical abnormalities in the renal development of those with BBS1 mutations. The parents of the fetus did not consent to post-induction autopsy, so it is not clear whether the fetus had other clinical manifestations associated with BBS1 mutations.
WES has the advantage of being able to rapidly and efficiently detect all potentially pathogenic mutations at once . However, its huge data output also brings great challenges when it comes to bioinformatics analysis and clinical interpretation . In this study, WES also revealed heterozygous variation of c.2704G>A (NM_00108052.2.2, p.Asp902Asn) in exon 22 of the fetus’s CC2D2A gene. This gene is primarily involved in the development of COACH syndrome (OMIM:216360), Joubert syndrome 9 (OMIM:612285), and Meckel syndrome 6 (OMIM:612284).
COACH syndrome is an autosomal, recessive, inherited disorder , with intellectual disability, ataxia (due to cerebellar hypoplasia), and liver fibrosis as typical clinical features. Joubert syndrome is also an autosomal, recessive, inherited disease , which manifests clinically through cerebellar ataxia, ocular movement dysfunction, vermis hypoplasia, and thickening of the upper cerebellar foot. Meckel syndrome, another autosomal recessive inherited disease , is a fatal multiple congenital anomaly disorder with clinical features that include brain malformation, polycystic kidney malformation, polydactyl deformity, cleft lip and palate, cardiac abnormality, central nervous system malformation, liver fibrosis and bone dysplasia. Heterozygous variation of c.2704G>A (NM_00108052.2.2, p.Asp902Asn) in exon 22 of the CC2D2A gene was also found in the parents of the fetus. According to ACMG guidelines, c.2704G>A was identified as a significant unknown mutation. Further study is needed to determine if the heterozygous variation of c.2704G>A is related to congenital renal dysplasia, along with more relevant future case reports.