ClinVar Genomic variation as it relates to human health

The copy number loss of 11q14.1q14.3 involves numerous protein-coding genes, including FZD4 (OMIM 604579), EED (OMIM 605984), TMEM126B (OMIM 615533), and HIKESHI (OMIM 614908). Haploinsufficiency of FZD4 is associated with autosomal dominant exudative vitreoretinopathy-1 (EVR1; OMIM 133780), which is characterized by the incomplete development of the retinal vasculature. Its clinical appearance varies considerably, with severely affected patients often registered as blind during infancy, whereas mildly affected patients with few or no visual problems may have such a small area of avascularity in their peripheral retina that it is visible only by fluorescein angiography. Additionally, heterozygous missense variants of FZD4 are associated with autosomal dominant retinopathy of prematurity (OMIM 133780). Heterozygous missense (potentially loss-of-function) variants of EED are associated with autosomal dominant Cohen-Gibson syndrome (COGIS; OMIM 617561), which is characterized by increased somatic parameters apparent from birth and associated with variable intellectual disability (ID). Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia. Biallelic missense variants of HIKESHI are associated with autosomal recessive hypomyelinating leukodystrophy-13 (HLD13; OMIM 616881), which is characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. More variable neurologic deficits, such as visual impairment, may also occur. Some patients may experience cardiac failure during acute illness. Biallelic missense variants of TMEM126B are associated with autosomal recessive mitochondrial complex I deficiency nuclear type 29 (MC1DN29; OMIM 618250), which presents with exercise intolerance and muscle weakness in childhood or adolescence. There are two additional genes in this copy number loss that are associated with autosomal recessive disorders: CTSC (OMIM 602365) and TMEM126A (OMIM 612988). While DLG2 (OMIM 603583) is not currently associated with an OMIM phenotype, there is emerging information suggesting deletions of this gene may be a risk factor for neurodevelopmental disorders (Reggiani 2017, Di Gregorio 2017). Sequence variants and intragenic deletions of DLG2 have also been observed in patients with schizophrenia Kushima 2017, Ingason 2015, Georgieva 2014). As copy number losses of this interval have been associated with a clinical phenotype, and there are no similar copy number losses of this region in the general populations of the Database of Genomic Variants, based on current medical literature and gene content, this copy number variant (CNV) is interpreted as pathogenic. References: Di Gregorio et al., Clin Genet. 2017 Oct;92(4):415-422. PMID: 28295210 Georgieva et al., Hum Mol Genet. 2014 Dec 15;23(24):6677-83. PMID: 25055870 Ingason et al., Transl Psychiatry. 2015 Oct 13;5(10):e656. PMID: 26460480 Kushima et al., Mol Psychiatry. 2017 Mar;22(3):430-440. PMID: 27240532 Reggiani et al., Genome Med. 2017 Jul 19;9(1):67. PMID: 28724449