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Annual Review of Genomics and Human Genetics

Volume 21, 2020

Genomically Aided Diagnosis of Severe Developmental Disorders

Abstract

Our ability to make accurate and specific genetic diagnoses in individuals with severe developmental disorders has been transformed by data derived from genomic sequencing technologies. These data reveal both the patterns and rates of different mutational mechanisms and identify regions of the human genome with fewer mutations than would be expected. In outbred populations, the most common identifiable cause of severe developmental disorders is de novo mutation affecting the coding region in one of approximately 500 different genes, almost universally showing constraint. Simply combining the location of a de novo genomic event with its predicted consequence on the gene product gives significant diagnostic power. Our knowledge of the diversity of phenotypic consequences associated with comparable diagnostic genotypes at each locus is improving. Computationally useful phenotype data will improve diagnostic interpretation of ultrarare genetic variants and, in the long run, indicate which specific embryonic processes have been perturbed.

Keyword(s): aneuploidy, de novo mutation, developmental disorders, differentiation, embryogenesis, evolution, genomic constraint, malformations, pediatric, phenotype
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2020-08-31
2024-04-25
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Genomically Aided Diagnosis of Severe Developmental Disorders
Annual Review of Genomics and Human Genetics 21, 327 (2020); https://doi.org/10.1146/annurev-genom-120919-082329
/content/journals/10.1146/annurev-genom-120919-082329
/content/journals/10.1146/annurev-genom-120919-082329
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