ClinVar Genomic variation as it relates to human health

The copy number gain of 5q35.2q35.3 involves multiple protein-coding genes, including NSD1 (OMIM 606681), SLC34A1 (OMIM 182309), and F12 (OMIM 610619). Haploinsufficiency of NSD1 is associated with Sotos syndrome 1 (OMIM 117550). The NSD1 gene, however, is not currently classified as triplosensitive, although it is contained within the shortest region of overlap within a larger 5q35 recurrent region associated with reversed Sotos syndrome phenotype, commonly including short stature, microcephaly, delayed bone age, and developmental delay/intellectual disability. Case reports with smaller overlapping duplications of this region that include NSD1 were described with Silver-Russell syndrome (SRS), and three with reverse Sotos syndrome (Kirchhoff et al., Eur J Med Genet. Jan-Feb 2007;50(1):33-42. PMID: 17090394; Reis et al., Genet Mol Res. 2017 Jan 23;16(1). PMID: 28128410; Sachwitz et al., Clin Genet. 2017 Jan;91(1):73-78. PMID: 27172843; Rosenfeld et al., Mol Syndromol. 2013 Jan;3(6):247-54. PMID: 23599694). The individual with SRS carried a de novo 381 Kb duplication. Two individuals with reverse Sotos syndrome carried de novo duplications and one carried a maternally inherited duplication. All patients had phenotypes involving growth retardation and facial anomalies. Thus, the clinical significance of this copy number variant (CNV) is likely pathogenic. Additional information on this duplication as follows: heterozygous sequence variants of SLC34A1 cause hypophosphatemic nephrolithiasis/osteoporosis-1 (OMIM 612286), heterozygous activating variants of F12 cause hereditary angioedema-3 (OMIM 610618), and heterozygous sequence variants of DDX41 have been associated with increased susceptibility to multiple types of familial myelo- and lymphoproliferative neoplasms (OMIM 616871).