Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy

Ivan Y Iourov; Svetlana G Vorsanova; Sergei A Korostelev; Maria A Zelenova; Yuri B Yurov

doi:10.1186/s13039-015-0182-z

Long contiguous stretches of homozygosity spanning shortly the imprinted loci are associated with intellectual disability, autism and/or epilepsy

Mol Cytogenet. 2015 Oct 15:8:77. doi: 10.1186/s13039-015-0182-z. eCollection 2015.

Authors

Ivan Y Iourov¹, Svetlana G Vorsanova², Sergei A Korostelev³, Maria A Zelenova², Yuri B Yurov²

Affiliations

¹ Mental Health Research Center, 117152 Moscow, Russia ; Separated Structural Unit "Clinical Research Institute of Pediatrics", Russian National Research Medical University named after N.I. Pirogov, Ministry of Health of Russian Federation, 125412 Moscow, Russia ; Department of Medical Genetics, Russian Medical Academy of Postgraduate Education, 123995 Moscow, Russia.
² Mental Health Research Center, 117152 Moscow, Russia ; Separated Structural Unit "Clinical Research Institute of Pediatrics", Russian National Research Medical University named after N.I. Pirogov, Ministry of Health of Russian Federation, 125412 Moscow, Russia.
³ Research Centre for Medical Genetics, 115478 Moscow, Russia.

Abstract

Background: Long contiguous stretches of homozygosity (LCSH) (regions/runs of homozygosity) are repeatedly detected by single-nucleotide polymorphism (SNP) chromosomal microarrays. Providing important clues regarding parental relatedness (consanguinity), uniparental disomy, chromosomal recombination or rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Additionally, despite being relevant to imprinting, LCSH at imprinted loci have not been truly addressed in terms of pathogenicity. In this study, we examined LCSH in children with unexplained intellectual disability, autism, congenital malformations and/or epilepsy focusing on chromosomal regions which harbor imprinted disease genes.

Results: Out of 267 cases, 14 (5.2 %) were found to have LCSH at imprinted loci associated with a clinical outcome. There were 5 cases of LCSH at 15p11.2, 4 cases of LCSH at 7q31.2, 3 cases of LCSH at 11p15.5, and 2 cases of LCSH at 7q21.3. Apart from a case of LCSH at 7q31.33q32.3 (~4 Mb in size), all causative LCSH were 1-1.5 Mb in size. Clinically, these cases were characterized by a weak resemblance to corresponding imprinting diseases (i.e., Silver-Russell, Beckwith-Wiedemann, and Prader-Willi/Angelman syndromes), exhibiting distinctive intellectual disability, autistic behavior, developmental delay, seizures and/or facial dysmorphisms. Parental consanguinity was detected in 8 cases (3 %), and these cases did not exhibit LCSH at imprinted loci.

Conclusions: This study demonstrates that shorter LCSH at chromosomes 7q21.3, 7q31.2, 11p15.5, and 15p11.2 occur with a frequency of about 5 % in the children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations appears to be the most common one among children with neurodevelopmental diseases. Finally, since LCSH less than 2.5-10 Mb in size are generally ignored in diagnostic SNP microarray studies, one can conclude that an important epigenetic cause of intellectual disability, autism or epilepsy is actually overlooked.

Keywords: Autism; Bioinformatics; Epigenetics; Epilepsy; Intellectual disability, Congenital anomalies; Long continuous stretches of homozygosity.