Genomic screening and causes of rare disorders

Abstract: Congenital disorders affect approximately 3-4% of all children and often cause chronic disabilities with significant impact on the lives of affected individuals and their families as well as on the health-care system. These disorders constitute a large and heterogeneous group of disorders with most of them being rare (prevalence <1/2000) and having an underlying genetic basis. Understanding of the molecular etiology and phenotypic spectrum has expanded during recent years. Over the past ten years, it has been shown that different types of causative genetic variants, such as single nucleotide variants, small indels or copy number variants, can be detected in many patients with congenital disorders. However, much remain to be explored concerning the spectrum of genetic variants and phenotypes associated to these disorders. The studies in the thesis have focused on determining the molecular etiology of rare congenital disorders and delineating the phenotypes associated with these disorders. In order to achieve this, phenotypic investigations combined with genetic screening through clinical array-CGH and whole exome sequencing, followed by a strategy for evaluation, were performed in selected families. Twenty families with parental kinship and children affected by presumed autosomal recessive disorders and one additional family with a de novo dominant disorder were included in the studies. By this approach, a molecular diagnosis could be determined in 15 out of 21 families. With the results from the studies, the gene PIGT was established as a novel disease gene, the genes TFG and KIAA1109 were confirmed as novel disease genes and additional candidate genes for congenital disorders were identified. Furthermore, the phenotypes for disorders associated with the genes MAN1B1, RIPK4 and FLVCR2 were expended and the spectrum of pathogenic variants in the gene SATB2 was broadened. The overall conclusions from the studies were that WES is a very powerful method for the identification of disease-causing variants in consanguineous families and that the diversity of AR diseases is enormous with many of the identified disorders being extremely rare. An additional conclusion is that a detailed phenotypic assessment is crucial for interpretation of data from large-scale genetic screening and for ascribing pathogenicity to the identified variants. Moreover, the full spectrum of genetic variants, including sequence alterations and CNVs, should be considered for the etiology of rare disorders. The results altogether add detail to the clinical presentations of the given disorders and expand the number of genes and genetic variants with a presumed or established causal association to congenital disorders. Ultimately, this may increase the chances to achieve a genetic diagnosis for future patients.