Unmasking a recessive allele by a deletion: Early prenatal diagnosis of Bardet‐Biedl syndrome in a Chinese family

Abstract

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by retinal dystrophy, obesity, polydactyly, intellectual disability, renal dysfunction, and hypogonadism. It has been classified as a ciliopathy, notable for extensive allelic and genetic heterogeneity. Before birth, enlarged/cystic kidneys and polydactyly are the hallmark signs of BBS, and can be identified by second-trimester sonography. However, BBS has seldom been diagnosed prenatally at the first trimester of gestation. We here report a prenatal BBS case found on ultrasound in early pregnancy. A 24-year-old G2P0A1 woman was referred to our center for a routine first-trimester scan. The couple was unrelated and both partners were healthy. Her first pregnancy was interrupted at 18 weeks gestation 2 years previously because of fetal enlarged kidneys and polydactyly in both hands. Amniocentesis reported a 46,XX,del (4)(q26q27) karyotype. Accordingly, single nucleotide polymorphism chromosomal microarray detected a 6.71-Mb deletion on 4q26q27 (arr[hg19] 4q26q27(116534641-123 247 549) × 1), classified as a variant of unknown significance (VOUS). Family studies revealed the same karyotype in the mother, and a normal chromosome constitution in the father. At this referral, fetal ultrasonography measured a normal nuchal translucence (NT) (1.2 mm) with a crown-rump length of 60 mm. However, the anatomic survey demonstrated postaxial polydactyly in the right hand (Figure 1A). No other anomalies were noted. Considering the recurrence of fetal phenotype, an autosomal recessive disorder was suspected. The array result of the previous pregnancy was then carefully reviewed. The 6.71-Mb 4q26q27 deletion consists of nine OMIM genes: TRPC3, BBS7, EXOSC9, KIAA1109, MYOZ2, NDNF, PRDM5, PRSS12, and SEC24D; among these, the BBS7 is one of multiple genes causing BBS which has the presentation of renal anomaly and polydactyly. We reasoned that the maternal deletion might have unmasked a paternally inherited recessive variant in that region on the non-deleted chromosome 4. To confirm this speculation, chorionic villus sampling (CVS) was performed, and trio whole exome sequencing (WES) was used. As expected, microarray detected the same 4q26q27 deletion (Figure S1), and WES reported a heterozygous NM_176824:c.1002del (p.N335Ifs*47) variant of BBS7 in the father, wild allele in the mother, and a “homozygous” state of the variant in the fetus (Figure 1B). No other variants, especially in the genes included in 4q26q27, were detected. The archived fetal DNA of the previous pregnancy was achieved, and targeted Sanger sequencing confirmed the presence of the “homozygous” c.1002del variant. The parents elected to terminate the pregnancy at 18 weeks when a repeat scan showed bilateral enlarged kidneys (Figure 1C). Postnatal autopsy confirmed the prenatal sonographic findings. Given the incomplete clinical manifestations available on ultrasound, early prenatal diagnosis of BBS is challenging if there is not a family history. A large study based on 45 BBS fetuses found that postaxial polydactyly and renal anomalies were the most prevalent signs of BBS. However, identification of renal malformations such as hyperechogenic and/or cystic kidneys is impossible at the first trimester. The literature suggests that the majority of limb abnormalities detected prenatally can be identified at the first trimester. Detection of limb abnormalities is important because they are often associated with serious disorders, which may be even more likely in fetuses with other abnormalities. In conjunction with a thorough reproductive history analysis, the timely identification of polydactyly led to early prenatal diagnosis of BBS in the present family. As such, a more detailed ultrasound should be considered at the time of NT measurement in the case of a previous pregnancy with fetal limb anomalies. An early prenatal diagnosis would benefit pregnancy management. In the present study, the 6.71 Mb deletion itself is not pathogenic. However, whenever a deletion occurs, any recessive variant on the non-deleted homologous chromosome would become unmasked, and resulting in the related disorders. Indeed, there is anecdotal evidence for unmasking a recessive disease by either recurrent, de novo or familial deletions. In everyday practice, the finding of fetal deletional VOUS is a major issue given its uncertainty. Our case indicates that it may Received: 16 January 2021 Revised: 31 January 2021 Accepted: 7 February 2021