International Journal of Molecular and Cellular Medicine (IJMCM)

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17p13.3 microduplications are rare copy number variations (CNVs) associated with variable phenotypes, including facial dysmorphism, developmental delay, intellectual disability, and autism. Typically, when a recognized pathogenic CNV is identified, other genetic factors are not considered. We investigated via whole-exome sequencing the presence of additional variants in four carriers of class I 17p13.3 microduplications. A 730 kb 17p13.3 microduplication was identified in two half-brothers with intellectual disability, but not in a third affected half-brother or blood cells from their normal mother (Family A), thus leading to the hypothesis of maternal germline mosaicism. No additional pathogenic variants were detected in Family A. Two affected siblings carried maternally inherited 450 kb 17p13.3 microduplication (Family B); the three carriers of the microduplication exhibited microcephaly and learning disability/speech impairment of variable degrees. Exome analysis revealed a variant of uncertain significance in RORA, a gene already linked to autism, in the autistic boy; his sister was heterozygous for a CYP1B1 pathogenic variant that could be related to her congenital glaucoma. Besides, both siblings carried a loss-of-function variant in DIP2B, a candidate gene for intellectual disability, which was inherited from their father, who also exhibited learning disability in childhood. In conclusion, additional pathogenic variants were revealed in two affected carriers of class I 17p13.3 microduplication (Family B), probably adding to their phenotypes. These results provided new evidence regarding the contribution of RORA and DIP2B to neurocognitive deficits, and highlighted the importance of full genetic investigation in carriers of CNV syndromes with variable expressivity. Finally, we suggest that microcephaly may be a rare clinical feature also related to the presence of the class I 17p13.3 microduplication.

Keywords: 17p13.3 microduplication, microcephaly, neurodevelopmental disorder, autism, variable expressivity, RORA, CYP1B1, DIP2B

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