Putative relation between Autism Spectrum Disease [ASD] and Hereditary Multiple Exostosis [HME] investigated by Whole Genome Next Generation Sequencing [WGNGS] &amp; Comparative Genome Analyses in a family with ASD and HME with <i>EXT-1</i> Mutation
Creators: name: Kambouris, Marios
Publisher: name: F1000Research
Year: 2016

description: A family with two male children affected with ASD and HME as well as an unaffected female child, was studied to elucidate the Genetic basis of ASD in the family and a possible relation between ASD &amp; HME. The father and both male children are clinically affected by HME and carry the known pathogenic <i>EXT1</i> 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 <i>EXT1</i> mutation. Irie <i>et al.</i>, [<i>PNAS, 109</i>: 5052–5056, 2012] reported that <i>EXT1 </i>knock-out, Heparan Sulfate deficient mice exhibit Autism-like socio-communicative deficits and stereotypies suggesting a relation between Heparan Sulfate deficiency and ASD.<br><br>Whole-Genome SNP genotyping and CNV analyses did not detect aneuploidy or deletion/duplication defects. Fragile-X syndrome was also ruled-out. WGNGS for all members, comparative genome analyses and data mining were employed to decipher the following:The two ASD events are unrelated and are due to separate <i>De-novo</i> variants.The two ASD events are are due to a common <i>De-novo</i> variant because of parental gonadal mosaicism.The two ASD events are due to heterozygous variants inherited from both parents which in synergy exceed the ASD onset threshold in the affected offspring.The HME unaffected parent [mother] contributed heterozygous variants in the Heparan Sulfate biosynthesis pathway that in synergy with the <i>EXT1</i> mutation significantly compromised Heparan Sulfate biosynthesis and could be the genetic causes of ASD in the family [as is in the knock-out mice].Only exonic and splice-site variants of &gt;20X coverage were considered, prioritized according to increasing population frequency (0-1%) and damaging according to mutation effect prediction models.One <i>De novo</i> variant is shared between the two affected children, demonstrating parental gonadal mosaicism.  Its contribution to ASD is unknown.No clinically significant X-linked variants are shared between the two affected children.No variants in known ASD related genes are shared between the two affected children.A small number of heterozygous damaging variants are shared between the two affected children transmitted from either parent.  Their contribution to ASD is unknown.The ASD-like behavior in mice is associated with compromised Heparan Sulfate biosynthesis due to complete lack of the EXT1 protein while humans with HME and ASD do have one functional EXT1 copy.No significant heterozygous damaging variants in the Heparan Sulfate biosynthesis pathway were transmitted from the mother that in synergy with the EXT1 mutation could significantly compromise Heparan Sulfate biosynthesis [as in the knock-out mice] and cause ASD in the family.With HME incidence 1/50,000 and ASD incidence 1/100 patients with both conditions would be 1/5x106, justifying co-segregation of both conditions in rare individuals.ASD in this family is probably caused by still elusive Genetic, Epigenetic or other factors shared between the two affected children but not their father