ClinVar Genomic variation as it relates to human health

This copy number loss of 13q32.3q34 is expected to cause phenotypic and/or developmental abnormalities. Losses similar to the current deletion have been reported in patients exhibiting a broad spectrum of clinical features of 13q33-q34 deletion syndrome (OMIM 619148) with variable expressivity and incomplete penetrance including developmental delay, intellectual disability, facial dysmorphic features, anorectal/genitourinary and gastrointestinal tract malformations, congenital heart defect, skeletal abnormalities, hearing loss, and coagulation disorders (Gambin 2017, Levy 2018, Quelin 2009). The copy number loss of 13q32.3q34 involves multiple protein-coding genes, including ZIC2 (OMIM 603073), NALCN (OMIM 611549), and FGF14 (OMIM 601515). Haploinsufficiency of ZIC2 is associated with autosomal dominant holoprosencephaly-5 (HPE5) (OMIM 609637). In addition, heterozygous sequence variants of NALCN are associated with congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) (OMIM 616266). Furthermore, heterozygous sequence variants of FGF14 are associated with autosomal dominant spinocerebellar ataxia-27 (SCA27) (OMIM 609307). There are multiple genes in this copy number loss that are associated with autosomal recessive disorders: NALCN, PCCA (OMIM 232000), TPP2 (OMIM 190470), ERCC5 (OMIM 133530), SLC10A2 (OMIM 601295), and LIG4 (OMIM 601837). There are no similar copy number losses of this region in the general populations of the Database of Genomic Variants. Thus, the clinical significance of this copy number variant (CNV) is pathogenic. References: Gambin et al., Genome Med. 2017;9(1):83. PMID: 28934986. Levy et al., Clin Genet. 2018;93(6):1141-1147. PMID: 29508392. Quelin et al., Eur J Med Genet. 2009;52(1):41-6. PMID: 19022413.