Unexpected Inheritance Patterns in a Large Cohort of Patients with a Suspected Ciliopathy

Abstract

Ciliopathies are rare genetic disorders caused by dysfunction of the primary or motile cilia. Their mode of inheritance is mostly autosomal recessive with biallelic pathogenic variants inherited from the parents. However, exceptions exist such as uniparental disomy (UPD) or the appearance of a de novo pathogenic variant in trans of an inherited pathogenic variant. These two genetic mechanisms are expected to be extremely rare, and few data are available in the literature, especially regarding ciliopathies. In this study, we investigated 940 individuals (812 families) with a suspected ciliopathy by Sanger sequencing, high-throughput sequencing and/or SNP array analysis and performed a literature review of UPD and de novo variants in ciliopathies. In a large cohort of 623 individuals (511 families) with a molecular diagnosis of ciliopathy (mainly Bardet-Biedl syndrome and Alström syndrome), we identified five UPD, revealing an inherited pathogenic variant and five pathogenic variants of de novo appearance (in trans of another pathogenic variant). Moreover, from these ten cases, we reported 15 different pathogenic variants of which five are novel. We demonstrated a relatively high prevalence of UPD and de novo variants in a large cohort of ciliopathies and highlighted the importance of identifying such rare genetic events, especially for genetic counseling.

Figure 1

Identification of five uniparental isodisomies (iUPD) and five de novo variants among 623 positive cases for ciliopathies genes. (a) Pedigrees and SNP array profiles of the five iUPD implicated in AS (ALMS1), BBS (BBS2 and BBS12), and Mainzer-Saldino syndrome (IFT140). The SNP array data is separated into two panels for each patient. The upper panel shows the B-allele frequency representing the variant status (an allelic composition measurement) for each SNP position. Heterozygous SNP are in the middle (~0.5), while homozygous are at either 0 or 1. This can be used to highlight the loss of heterozygosity regions for all the cases except XV.30. The lower panel shows the log R ratio to identify copy number variants (CNV). Above each chromosome map, a “^∗” indicates the gene position. (b) Pedigrees of the five individuals carrying a de novo variant implicated in AS (ALMS1) and BBS (BBS1 and BBS4).