ClinVar

Description

The copy number gain of 17p13.3 involves multiple genes including YWHAE (OMIM 605066), BHLHA9 (OMIM 615416), CRK (OMIM 164762) and PRPF8 (OMIM 607300) and is expected to cause phenotypic and/or developmental abnormalities. Duplications of this region, involving YWHAE but not PAFAH1B1, have been associated with the class I type of chromosome 17p13.3 duplication syndrome (OMIM 613215) featured with intellectual impairment, autism, occasional structural brain abnormalities and possibly early overgrowth. Incomplete penetrance and highly variable expressivity are characteristic of this duplication syndrome. Inter- and intrafamilial variability is typical, especially in cognitive development, and appears to be at least partially dependent on the size of the duplication and genes involved. Duplications of YWHAE and flanking genes such as CRK are most commonly associated with autism spectrum disorders (Curry et al., Am J Med Genet A. 2013 Aug;161A(8):1833-52. PMID: 23813913; Henry et al. Eur J Med Genet. 2016 Oct;59(10):512-6; PMID: 27633569). A de novo 231 Kb gain including YWHAE and CRK was reported in a patient with developmental delay (Crippa et al., Front Genet. 2019 Oct 15;10:955. PMID: 31749829). The present gain interval also overlaps the region, including BHLHA9, associated with split-hand/foot malformation with long bone deficiency-3 (OMIM 612576), which is less than 50% penetrant and shows markedly variable expressivity. In addition, heterozygous pathogenic sequence variants of PRPF8 (missense and truncating) have been associated with autosomal dominant retinitis pigmentosa 13 (OMIM 600059).