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The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic  de novo , rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in  PKD1L1  and  ZIC3  were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in  LMBRD1  and  DNAH17 , respectively, were prioritized. In another family, an ultra-rare  de novo  variant in  WDR47  was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in  WDR47 , but no further individuals with biallelic variants in  DNAH17  or  LMBRD1 . Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes  PKD1L1  and  ZIC3  and suggests  DNAH17 ,  LMBRD1 , and  WDR47  as potential genes involved in laterality defects.

Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes