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Identification of Novel Alleles of a Human-specific Neocortical Gene, NOTCH2NL Associated with Neurodevelopmental Disorders

*N. R. HEYER1,4, C. BOSWORTH1,2, G. MANTALAS1,3, D. HAUSSLER1,2,5, S. SALAMA1,2,5;

1.Genomics Inst., 2.Biomolecular Engin. and Bioinformatics Dept., 3.Molecular, Cell. and Developmental Biol. Dept., Univ. Of California, Santa Cruz, Santa Cruz, CA; 4.California State University, Monterey Bay, Seaside, CA; 5.Howard Hughes Med. Inst., San Francisco, CA

The three NOTCH2NL genes, NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC are implicated in 1q21.1 distal deletion/duplication syndromes, which can result in neurodevelopmental disorders (NDs) such as Autism, ADHD, Schizophrenia, Microcephaly, and Macrocephaly. Previous work demonstrated that NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC are located within the typical deletion and duplication region, and functional analysis suggested a role for NOTCH2NL in regulating neural stem cell expansion in the developing cerebral cortex.1,2

We aim to understand the differing relationships of specific NOTCH2NL alleles with NDs. By understanding their function, we open the possibility for a future clinical diagnostic model to predict the likelihood of NDs resulting from specific NOTCH2NL allele combinations. To do this, we first developed an analysis pipeline to determine the NOTCH2NLA, NOTCH2NLB, and NOTCH2NLC alleles present in individual samples, as well as the related genes NOTCH2NLR and NOTCH2. This pipeline utilizes targeted linked read sequencing of high molecular weight genomic DNA, that allows us to obtain the high-depth and base-accurate reads needed to assemble genes in the presence of short tandem repeats.1 Reads are grouped based on self-similarity and classified into groupings corresponding to each gene in the family. Groupings are then translated in silico into the corresponding amino acid sequence, allowing for the identification of protein variants. We used this pipeline to analyze the alleles of the NOTCH2NL gene family in a genetically diverse pool of individuals from the Thousand Genome Project3, sequenced by Genome in a Bottle4 (n = 6),in our lab (n = 13), and NA12878 directly form 10X. We discovered three novel NOTCH2NL alleles, including a frameshift mutation in NOTCH2NLC, which was the result of a deletion of a single base pair in the last exon, in the region coding for novel sequence relative to the parent NOTCH2 gene. The analysis and discovery of these new alleles are promising, as this is the first step in determining the relative neurodevelopmental function of the different loci, and alleles. We plan to take advantage of large genome sequencing data sets such as those generated by the Autism Genetics Resource and the Simons Foundation Autism Research Initiative to correlate NOTCH2NL alleles with NDs. We foresee this work eventually allowing for the development of a clinical model that could allow for earlier detection of these disorders and, in turn, could help to create better patient outcomes.

  1. Fiddes IT et al. (2018) Cell. 173:1356-1369.e22.
  2. Suzuki IK et al. (2018) Cell. 173:1370-1384.e16.
  3. Auton A et al. (2015) Nature. 526:68.
  4. Zook JM et al. (2016) Scientific Data. 3:160025.