The frontiers of sequencing in undiagnosed neurodevelopmental diseases

Abstract

Characterized by impairments in brain and central nervous system development, neurodevelopmental diseases causes are highly heterogeneous. Although many of these diseases are individually rare, collectively more than 3% of the children are reported to be affected with a type of neurodevelopmental diseases worldwide, and many remain undiagnosed even with current genomic tools. Identifying the genetic causes of these diseases allows better clinical management and expands our understanding of human neurodevelopment. Over the past decade, expansion of genomic sequencing and some methodologic improvements have improved molecular diagnostic yield as well as the discovery of novel genetic causes for wide spectrum of neurodevelopmental diseases. Here we review the current diagnostic workflow and propose ways of improving the diagnostic yield.

Figure 1.

Summary of available genomic tests for diagnosing rare neurodevelopmental diseases. The published diagnostic rate (DR) for each test is indicated. CMA: chromosomal microarray, CNV: copy number variant, SNV: single nucleotide variant, INDEL: small insertion and deletion, SV: structural variants including CNV.

Figure 2.

Approximate number of novel genes discovered to be associated with an NDD (stacked bar) and Mendelian disease (blue line) per year (primary Y-axis) and cumulatively (secondary Y-axis and yellow and green curved line graph). For NDD, the genes were separately counted for autosomal dominant (NDD-AD), autosomal recessive (NDD-AR) and X-linked (NDD-X) disease genes. Estimation was made by counting the number of genes deposited in the Human Gene Mutation Database (HGMD) for the first time for each year. Only the disease-causing mutations (DM) were considered. (A) Number of autosomal dominant (AD), autosomal recessive (AR) and X-linked genes for NDD and all Mendelian disease genes cumulatively.

Figure 3.

Minor allele frequency distribution of pathogenic/likely pathogenic variants in autosomal recessive neurodevelopmental diseases. Neurodevelopmental disease gene list was created by querying OMIM for genes associated with autosomal recessive diseases involving developmental delay, intellectual disability, mental retardation, seizures or epilepsy. Variants that were in HGMD as disease causing and classified as pathogenic or likely pathogenic in ClinVar were selected. gnomAD was used to extract MAF information on these variants.