oa Putative Relation Between Autism Spectrum Disease & Hereditary Multiple Exostosis Investigated by Whole Genome Sequencing & Comparative Genome Analyses in a Family with ASD and HME with EXT-1 Mutations

A family with two male children affected with ASD and HME as well as an unaffected female child, was studied to identify the Genetic basis of ASD in the family and the possible relation between ASD & HME.

Irie et al., [PNAS, 109: 5052–5056, 2012] reported that Heparan Sulfate deficient mice due to inactivating EXT-1 mutations exhibit Autism-like socio-communicative deficits and stereotypies suggesting a relation between MHE and ASD. The father and both male children are clinically affected by HME and carry the known pathogenic EXT-1 c.C1018T/p.R340C dominant mutation. Both male children are also affected by ASD; the father is not. The mother and the female child are not affected either by HME or ASD and do not carry the EXT-1 mutation.

Whole-Genome SNP genotyping and CNV analyses did not detect aneuploidy or deletion/duplication defects as possible ASD causes. WGNGS for all members, comparative genome analyses and data mining were as follows: [Only exonic variants considered, prioritized according to increasing population frequency (0–1%), damaging effects according to mutation prediction models and will be presented in table format].

1. The two ASD events are unrelated and are due to de-novo variants. Trio analyses identified 72 de-novo variants in the first affected child and 56 in the second. Twelve were in common

2. The two ASD events are due to heterozygous variants inherited from both parents which in synergy exceed a disease onset threshold in the affected offspring. Eighty father-to-son and 69 mother-to-son heterozygous variants shared between the affected males were identified.

4. The HME unaffected parent [mother] contributed heterozygous variants in the Heparan Sulfate biosynthesis pathway that in synergy with the EXT-1 mutation could be the genetic causes of ASD in the family.

WGNGS and comparative genome analyses were utilized to decipher the possible relationship between HME and ASD in this unique family with members affected by both disorders.