Concomitant CNVs in healthy carriers with 7q31.1 microdeletions may suppress intellectual disability and autism spectrum disorders phenotype

Introduction About 66% of chromosomal microdeletions and microduplications associated with pathological conditions are inherited [Smajlagić D. et al., 2021]. The mechanisms of incomplete penetrance and variable expressivity of CNV are not fully understood. The presence of concomitant CNVs in the genome of healthy parents may have a modifying effect. Objectives Identification of additional CNVs in healthy carriers with 7q31.1 microdeletions. Methods CNVs were revealed by Agilent Technologies 60K microarray and confirmed by qPCR. Results We examined 3 families with inherited 7q31.1 microdeletions affecting only the IMMP2L gene, which is associated with intellectual disability, developmental delay and autism spectrum disorders. Family 1: Proband has intellectual disability, developmental delay, sensorimotor alalia. Microdeletion was inherited from the father, and a healthy sibling is also a carrier of rearrangement. In sibs, additional CNVs were identified: arr[hg19]: 4q31.21(144722583_144939143)×3; 9p12p11.2(43588066_43836428)×3; 16p11.2(32066967_33773163)×1; and 17q21.31(44199517_44577208)×3. Family 2: Proband suffers from development delay, speech disorder and autism. Microdeletion was of paternal origin. The father additionally demonstrated microduplication 16p11.2p11.1(33967926-35204414)×3. Family 3: Proband was diagnosed with development delay and cerebral palsy. The mother is a carrier of a similar 7q31.1 microdeletion; two concomitant CNVs were identified in her karyotype: 9p13.1(39176840_40614884)×3; and 16p11.2p11.1(32833891_35204414)×3. Thus, healthy parents in 3 families have CNV in a common region 16p11.2, which contains the TP53TG3 gene. It is important that TP53TG3 expression is associated with epistatic CNV-CNV interactions [Sun, Kardia 2010]. Conclusions Multiple CNVs in apparently healthy carriers of IMMP2L microdeltions may suppress disease phenotype due to the epistatic CNV-CNV interaction. This study was supported by Russian Science Foundation, grant no. 21-75-00112. Disclosure No significant relationships.