Expanding the genetic and phenotypic spectrum of skeletal dysplasias

Abstract

Skeletal dysplasias constitute a large and heterogeneous group of disorders, many causing disabilities with profound effects on the quality of life of the affected individuals and their families. Each individual skeletal dysplasia is rare, however, as more than 450 different disorders have been described, skeletal dysplasias as a group affect approximately three in 10 000 individuals. The age of onset for skeletal dysplasias ranges from prenatal to adult, but most of the affected individuals are diagnosed in childhood. Skeletal dysplasias mainly affect bone and cartilage, but symptoms may involve other organs, such as sensorineural hearing loss in Stickler syndrome, nephronophthisis in Sensenbrenner syndrome, and structural heart abnormalities in acromicric dysplasia. Therefore, most skeletal dysplasias can be defined as syndromes with a significant skeletal involvement.

Clinical diagnosis of skeletal dysplasias is based on meticulous phenotypic characterization, skeletal radiography (for pattern recognition) and genetic testing. Molecular diagnostics has improved significantly by massively parallel sequencing (MPS) technologies, such as whole exome and genome sequencing. However, even after extensive clinical phenotyping and advanced molecular analyses, many patients with congenital skeletal disorders still lack molecular diagnoses and many clinical entities are not well-characterized regarding their natural course and complications. Molecular diagnosis is important since it gives information about prognosis and recurrence risk, as well as, in some cases possibilities to offer targeted treatment, participation in clinical trials, and tailored medical follow-up. This thesis focuses on gene discovery, studies of previously clinically defined skeletal dysplasias with unknown genetic background and aims to improve the molecular analyses for patients with diagnoses which are difficult to solve.

In study I, we identify a novel pathogenic variant in ALG9, as the cause of a lethal skeletal syndrome in two families. In study II, we show that a variant in COL2A1 causes spondyloepiphyseal dysplasia type Stanescu. Study III shows that pathogenic variants in BMPER cause ischiospinal dysostosis (ISD), which is allelic to diaphanospondylodysostosis. In study IV, we describe a novel skeletal ciliopathy in four individuals with spondylometaphyseal dysplasia and thorax hypoplasia caused by pathogenic variants in KIAA0753. Finally, study V represents a cohort of 24 unrelated patients with skeletal ciliopathies, where we solve the genetic diagnoses in 83% of them. Here, we show two rare intronic variants and two exonic synonymous variants leading to aberrant splicing, which indicates that extended RNA studies are necessary to improve molecular diagnostics in some cases.

Altogether, the results of these studies expand the genetic and phenotypic spectrum of skeletal dysplasias and demonstrate that MPS technology in combination with meticulous phenotyping is a powerful method to discover disease-causing variants in patients with congenital skeletal disorders.