ClinVar Genomic variation as it relates to human health

This CNV is a 10.0 Mb deletion of 12q14.3-q21.1 on chromosome 12 (seq[GRCh37]del(12)(q14.3q21.1); chr12:g.65251705_75263379del), found in a de novo state. This loss encompasses over 65 genes and includes most of band 12q14.3, all of band 12q15 and most of band 12q21.1. The proximal breakpoint lies within the TBC1D30 gene and the distal breakpoint lies between the ATXN7L3B gene, which is encompassed by this event, and the KCNC2 gene, which is not encompassed by this event. Interstitial 12q deletions are rare and, in most cases, breakpoints are unique and non-recurrent. However, several partially overlapping and smaller losses falling within the boundaries of this event have been reported in individuals with phenotypes including prenatal and postnatal growth deficiency, neurodevelopmental disorders and variable congenital anomalies (Firth et al. 2009; Rehm et al. 2015). Smaller de novo and familial 12q14 deletions including LEMD3, associated with autosomal dominant osteopoikilosis and HMGA2, implicated in growth, have been reported in individuals with prenatal-onset growth deficiency, failure to thrive in early childhood, proportionate short stature, osteopoikilosis, learning disabilities, mild intellectual disability and dysmorphic features often described as Russell-Silver like (Fischetto et al. 2017; Heldt et al. 2018). Vergult et al. (2011) described three unique but overlapping deletions impacting band 12q15 and report developmental delay, nasal speech and hypothyroidism as core features associated with deletions of this region. Additional features in these individuals included variable dysmorphic features, thin habitus with slender fingers and toes, hypoplastic nails, mild scoliosis and, in one individual, a history of acute lymphoblastic leukemia (2011). Haploinsufficiency of CNOT2 may be a significant contributor to this phenotype, although other genes with evidence supporting an intolerance to loss of function are present in this interval (Uehara et al. 2019). Rare events which also extend into 12q21.1 are also rarely described and are associated with variable phenotypes (Schluth et al. 2008). This interval also includes WIF1, which has been reported as a candidate gene for a Nail-Patella like syndrome in a multi-generational family (Jones et al. 2017). Overlapping losses are not reported in control individuals. Based on the collective evidence, this CNV is classified as pathogenic.