Rare genetic conditions collectively affect approximately 5% of the population. More than 50% patients with suspected genetic disorders remain unsolved even after whole genome sequencing. Furthermore, for disorders with known genetic causes, the management and treatment options are usually limited.
Identification of novel diseases
We have led on identification of several rare genetic diseases and uncovered their mechanisms. These include –
Additionally, we have made significant contributions to international collaborations in the discovery of disease-genes including KMT2E, TET3.
We are performing systematic analysis of whole genome/exome data from several thousand patients with unsolved genetic disorders. This work is being done in collaboration with large national and international projects such as the 100,000 Genomes Project, Solve-RD, the Deciphering Developmental Disorders study and the Genomics of Developmental Disorders in India project.
Uncovering rare-diseases mechanisms
In collaboration with several research groups, locally and internationally, we have used cellular and organismal models to understand mechanisms of several diseases that has provided insights into fundamental biological processes (e.g. nuclear role of beta-actin and the role of POU3F2 in the neuroendocrine pathway for appetite); showed the diversity of disease causing genetic mechanisms (e.g. extreme phenotypic variability in RAC1-associated intellectual disability) and highlighted link of rare disease genes with commoner conditions (e.g. Leri’s pleonosteosis and systemic sclerosis); and led to development of treatments for some rare disorders (e.g. folinic acid treatment for DHFR deficiency).
We are using induced pluripotent stem cells (iPSCs) to study the basis of neuroloical disease (differentiating into cortical neurons) and malformations (differentiating into neural crest cells) in diseases caused by KMT2D mutations (with Prof Sue Kimber); Drosophila models to study the mechanism of RAC-related disorder (with Dr Tom Millard); zebrafish models to study EIF5A, FKBP4 and RLF-related disorders (with Dr Paul Kasher); mice models to study ACTB-related disordes (with Prof Adrian Woolf).
Contribution of copy number and non-coding variants in Mendelian disorders
Using data from copy number variants we have identified rare genetc disorder (for example see PMIDs 24442880, 26833329, 29220674,30245510, and 31079897) and showed that pathogenic CNVs are correlated with socio-economic status.
Natural history studies and clinical trials
Knowing phenotypic spectrum of rare conditions is crucial for their diagnosis and management. We have published the largest studies on Type 1 and Type 2 Kabuki syndromes, one of the commonest chromatin developmental disorders. We have shown that G6PC3 deficiency occurs in a phenotypic continuum and is characterized by severe congenital neutropenia with other haematological, urogenital and cardiovascular defects (see details). Showed that TPK1 mutations can cause both episodic encephalopathy thiamine metabolism dysfunction (OMIM 614458) and Leigh syndrome. We also showed that timely treatment with thiamine supplementation improves outcome (see details).
We are working on delineating phenotypic spectrum of several recently discovered chromatin remodelling disorders. This includes a national project on chromatin disorders as part of the NIHR BioResource for Rare Diseases. We are developing an international Expert-consensus management guidelines for Kabuki syndrome type 1. We are also a centre for a commercial clinical trial for Rett syndrome.