Short summary

Short stature in children is a common reason for referral to pediatric endocrinologists, but an underlying cause is not detected in approximately 70% of cases after clinical and laboratory evaluation. We postulate that Whole Genome Sequencing can contribute to the detection of genetic causes of short stature. The project will include method development and testing of long-read sequencing, and will aim to identify altered DNA methylation patterns and imprinting disorders.

Rationale

Short stature affects 2.3% of children, and growth impairment may cause an emotional burden for the children as well as concern for their parents. After clinical evaluation, it is not possible to identify an underlying cause in 70% of cases, and many of these children are classified as having idiopathic short stature (ISS). The technological development of sequencing techniques has expanded the understanding of genetic causes of growth disorders, and recent studies have proposed that 16-46% of children with ISS have monogenic defects. It has proved difficult to distinguish those at high risk of short stature as adults and to decide when genetic testing is indicated. Genetic causes of short stature are highly heterogeneous and may cause a wide phenotypic spectrum, ranging from isolated short stature to severe or syndromic conditions. Lack of specific characteristics makes diagnosis difficult, and analysis of single candidate genes is therefore often insufficient. A broader molecular testing strategy, such as Whole Genome Sequencing, may improve diagnostic yield. New long-read sequencing methods, e.g., nanopore sequencing, are expected to contribute to a better understanding of genomic imprinting by simultaneously detecting DNA modifications and sequence variants in the genome. The overall aim of the project is to identify genetic causes of short stature in children and to contribute to improving and developing the future assessment of children with growth impairment.

Description of the cohort

The cohort for the prospective study consist of children with short stature, recruited at the pediatric and clinical genetic departments in the region of Southern Denmark. In addition a cohort of children with short stature, followed in pediatric depts. in the region of Southern Denmark during the past 5 years, will be included in a descriptive study, where data are collected from medical records.

Data and biological material

Data from the patient journals. Blod samples (EDTA and PAX-gene).

Collaborating researchers and departments

Department of Clinical Genetics, Odense University Hospital

• Chief Consultant, Professor Lilian Bomme Ousager
• Cand. Scient. Martin Jakob Larsen
• Stine Bjørn Gram, MD, PhD.

HC Andersen Children and Youth Hospital, Odense University Hospital

• Dorte Hansen, MD