Investigation of the molecular aspects of growth and development

Poor growth is a relatively common problem in early childhood and in certain cases is known to be associated in the long term with an increased risk of medical problems including learning difficulties, diabetes, heart disease and certain types of cancer. In many cases the underlying cause is unknown. A significant contribution to our understanding of the processes involved in growth and development has come from the study of diseases that are rare in the general population but occur more frequently in isolated communities. Genes are the way that we store our hereditary information. These communities have the advantage that they have inherited the disease causing gene from a common ancestor making it far easier for scientists to identify it. The fellow will study two rare syndromes in the Amish community; a key component of each condition is insufficient growth. The aim will be to identify the disease causing gene(s) and to study their function. We hypothesise that analyzing the function of these genes will help us understand more about disorders of human growth which arise when the molecules involved do not function properly.

Disorders causing growth insufficiency are common in early childhood. Poor growth particularly during fetal development and early infancy is associated with an increased risk of morbidity. In the majority of cases the aetiological basis remains unidentified.

Two distinct disorders that result in growth failure have been identified in the Amish community. The first is microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) which is characterised by poor prenatal growth and subsequent postnatal growth restriction, microcephaly, dysmorphic facial features and specific skeletal abnormalities. The second condition appears to be new to medical science and is characterised by cerebral aneurysms, short stature and hoarse voice (ASH syndrome). Using extensive family cohorts we undertook a genome-wide high density SNP microarray study in affected and unaffected family members which led to the identification of novel gene loci for each condition; a ~3Mb region on chromosome 2 (MOPD), and a ~5.4Mb region on chromosome 20 (ASH syndrome).

This project aims to discover the genes and mutations responsible for these conditions, and investigate the molecular processes perturbed by these aberrations. We will use next generation sequencing technologies to undertake whole-exome sequence analysis of affected cases and verify the causative mutations by cosegregation and regional/non-region (non-Amish) control analysis, and investigate the causative (MOPD1) gene identified in other cases of primordial dwarfism. Following identification of the causative genetic variant(s) the study will be extended to tissue distribution analysis, protein localisation studies and pathway analysis.

The discovery of the causative genetic variants in these syndromes will make a significant contribution to our understanding of the molecular processes involved in growth and development. There is potential here to identify novel disease mechanisms and pathways involved in this important area. Additionally this study presents a rare opportunity to clinically characterise a novel disorder of growth and development namely ASH syndrome.