Large cohorts aid in genotype-phenotype analyses

The discovery of large numbers of families with changes in specific genes have proven invaluable in facilitating genotype-phenotype correlations for a handful of genes associated with neurodevelopment disorders (NDDs). Yet hundreds of risk genes have been implicated in NDDs and, for most, the contribution of these genetic changes to the phenotypic manifestations of NDDs remains unclear.

Efforts by the SPARK initiative and other neurodevelopmental disease consortiums have led to the successful recruitment and retention of large numbers of individuals with NDDs — and a recent study used consortium data to expand analyses of genotype-phenotype links. The multicenter study was led by SFARI Investigator Evan Eichler. This research was supported, in part, by a SFARI Targeted Award to Eichler.

Eichler’s team examined 63 NDD candidate genes where prior studies had suggested a recurrence of de novo mutations (DNMs) and assessed another 62 genes regarded as higher risk NDD candidates. These genes were examined in a large cohort of over 16,000 individuals with NDDs who were part of the international Autism Spectrum/Intellectual Disability (ASID) consortium (Stessman et al., Nat. Genet., 2017), and for which there was no prior exome or genome sequencing information available.

Using single-molecule molecular inversion probe (smMIP) targeted sequencing, the group analyzed coding and splicing regions within these candidate genes. Further analyses incorporated parent-child exome sequencing data not available at the outset of the study — including exome data from SPARK. This led to the identification of 48 genes with a significant excess of likely gene disruptive (LGD) and/or missense (MIS30) mutations and 90 enriched for DMNs — with 40 of these genes overlapping.

Importantly, for 25 of these genes, this represents the first evidence of ultra-rare LGD and/or MIS30 burden in a large-scale case-control study, with four also not previously linked to increases in DNMs.

The researchers were then able to go a critical step further for seven of these significant genes — linking genotype to phenotype. This leap was a direct result of work by the SPARK initiative and other consortiums to not just recruit, but also engage, families over the long-term. Such retention allowed Eichler and colleagues to re-connect with families to collect detailed clinical records. Comparing these clinical records to the genetic mutations in CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN and LEO1, the group was able to provide a better understanding of how these genes relate to specific clinical manifestations. Such work highlights the importance of ongoing efforts by SPARK and other neurodevelopmental consortiums to recruit and retain large numbers of affected families.


Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Wang T., Hoekzema K., Vecchio D., Wu H., Sulovari A., Coe B.P., Gillentine M.A., Wilfert A.B., Perez-Jurado L.A., Kvarnung M., Sleyp Y., Earl R.K., Rosenfeld J.A., Geisheker M.R., Han L., Du B., Barnett C., Thompson E., Shaw M., Carroll R., Friend K., Catford R., Palmer E.E., Zou X., Ou J., Li H., Guo H., Gerdts J. A., Avola E., Calabrese G., Elia M., Greco D., Lindstrand A., Nordgren A., Anderlid B.-M., Vandeweyer G., Van Dijck A., Van der Aa N., McKenna B., Hancarova M., Bendova S., Havlovicova M., Malerba G., Bernardina B.D., Muglia P., van Haeringen A., Hoffer M.J.V., Franke B., Cappuccio G., Lockhart P.J., Manning M.A., Liu P., Scheffer I.E., Brunetti-Pierri N., Rommelse N., Amaral D., Santen G.W.E., Trabetti E., Sedláček Z., Michaelson J., Pierce K., Courchesne E., Kooy R.F., SPARK Consortium, Nordenskjöld M., Romano C., Peeters H., Bernier R., Gecz J., Xia K., Eichler E.

Nat. Commun. 11, 4932 (September 30, 2020) PubMed

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