De novo interstitial 3p21.31p14.2 duplication in a boy with esophageal atresia, talipes equinovarus, and global developmental delay: a case report

Background: Imbalances of chromosome 3p produce phenotypes that depend on the position and direction of the dosage change. The classic duplication 3p syndrome arises from distal gains, whereas the proximal interstitial region spanning 3p21.31 to 3p14.3 has been characterized almost exclusively through deletions. Interstitial duplications confined to this gene-rich segment have not, to our knowledge, been reported. Case presentation: We describe a boy with a de novo interstitial duplication of 3p21.31p14.2, followed to 18 months of corrected age. He was born at 35 weeks for intrauterine growth restriction and had esophageal atresia, congenital cardiac findings, bilateral talipes equinovarus, and microcephaly. Examination showed central hypotonia, global developmental delay, and a dysmorphic gestalt. Brain magnetic resonance imaging showed mild ventriculomegaly with periventricular white matter hyperintensities. Exome sequencing was non-diagnostic; chromosomal microarray analysis identified a de novo gain, arr[GRCh38] 3p21.31p14.2(46424517_58792288)×3, of approximately 12.4 Mb encompassing SETD2, BSN, PBRM1, BAP1, and CACNA1D. Conclusion: This duplication does not substantially overlap previously reported proximal 3p gains and represents the near reciprocal of the 3p21.31p14.3 deletion. Interpreted as likely pathogenic, it expands the spectrum of proximal 3p imbalances and illustrates the interpretive challenge of gene-rich copy-number gains lacking established triplosensitivity.