Driving discovery of new genetic causes of developmental disorders

5 January 2015

Genome-wide analysis has identified new genetic causes of developmental disorders in children.

Developmental disorders are a broad group of conditions that include physical and mental problems and developmental delay. Geneticists have made great progress in recognising specific forms of disorder with shared phenotypic (observable) features, and in identifying underlying genetic causes; however, many such conditions show highly variable physical features and symptoms and may be very rare, in some cases potentially even unique to the individual. For this reason they are not easily diagnosed.

The Deciphering Developmental Disorders (DDD) project was established to attempt to increase rates of genetic diagnosis among a group of several thousand children with multiple malformations or serious physical or mental developmental delay, for whom a genetic cause was suspected but diagnosed. It has already reported on the first set of results from 1133 children and their parents, which showed increased rates of genetic diagnosis.

The latest publication by DDD researchers in the journal Nature reveals that using a genome-wide approach (in this case exome sequencing and array-based detection of chromosomal rearrangements) can identify groups of patients with related genetic disorders. Researchers sought genes with increased levels of potentially harmful new (de novo) mutations based on both their own and other available data. They also took into account other available information including similar phenotypic features.

A total of 12 new genes were strongly linked with developmental disorders in 35 patients. This not only helped to boost overall diagnostic rates, but also provided new insights into how changes in these genes may derail normal development and lead to varied forms of neurodevelopmental disorder, from learning disability to epilepsy and autism.

Importantly, the value of a genomic approach in addition to the traditional, phenotypic-driven approach to clinical discovery of new sub-groups of disease is demonstrated, especially for conditions that show very variable or non-specific features.

Overall the study nicely demonstrates the potential to boost diagnosis rates by using genome-wide approaches; whole genome sequencing, whilst creating significant further increases to the cost and complexity of analysis might reasonably expected to increase diagnosis still further.

The researchers themselves note the significant proportion of patients remaining undiagnosed despite their own genome-wide analysis and nationwide approach to sharing information, a vital element in clinical interpretation of genetic information to identify those changes with a significant likelihood of having caused the observed disease features. They emphasise that their findings underline the importance of data sharing, and urge the ’international sharing of minimal genotypic and phenotypic data’ as typified by the DECIPHER web portal to drive further expansion of genetic causes of developmental disorder.

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