ClinVar Genomic variation as it relates to human health

The copy number loss of 1q23.3 involves multiple protein-coding genes, including PBX1 (OMIM 176310), DDR2 (OMIM 191311), ATF6 (OMIM 605537), and NOS1AP (OMIM 605551). Heterozygous missense and loss-of-function variants and hemizygous whole and partial deletions of PBX1 are associated with congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED; OMIM 617641), which is an autosomal dominant highly pleiotropic developmental disorder characterized mainly by variable congenital anomalies of the kidney and urinary tract, sometimes resulting in renal dysfunction or failure, dysmorphic facial features, and abnormalities of the outer ear, often with hearing loss. Most patients have global developmental delay (Verbitsky 2019, Heidet 2017, Le Tanno 2017, Sun 2019, Fitzgerald 2021). In addition, heterozygous missense variants of DDR2 are associated with autosomal dominant Warburg-Cinotti syndrome, which is characterized by progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acroosteolysis (OMIM 618175). Biallelic missense and splice site variants of DDR2 are associated with autosomal recessive spondylometaepiphyseal dysplasia, short limb-hand type, which is a severe short-limb bone dysplasia (OMIM 271665). Furthermore, biallelic loss-of-function and missense variants of ATF6 are associated with achromatopsia 7, which is an autosomal recessive disorder resulting from lack of cone photoreceptor function. Affected individuals present from birth or early infancy with photophobia, nystagmus, severely reduced visual acuity, and color blindness (OMIM 616517). Biallelic missense and splice site variants of NOS1AP are associated with nephrotic syndrome type 22, which is an autosomal recessive renal disease characterized by onset of progressive kidney dysfunction in infancy. Affected individuals usually present with edema associated with hypoproteinemia, proteinuria, and microscopic hematuria. Renal biopsy shows effacement of the podocyte foot processes, glomerulosclerosis, and thickening of the glomerular basement membrane. The disease is steroid-resistant and progressive, resulting in end-stage renal disease usually necessitating kidney transplant (OMIM 619155). There are no similar copy number losses of this region in the general populations of the Database of Genomic Variants. Thus, based on current medical literature and gene content, this copy number variant (CNV) is classified as likely pathogenic. References: Fitzgerald et al., Am J Med Genet A. 2021 Jan;185(1):234-237. PMID: 33098248. Heidet et al., J Am Soc Nephrol. 2017 Oct;28(10):2901-2914. PMID: 28566479. Le Tanno et al., J Med Genet. 2017 Jul;54(7):502-510. PMID: 28270404. Sun et al., Taiwan J Obstet Gynecol. 2019 Mar;58(2):292-295. PMID: 30910156. Verbitsky et al., Nat Genet. 2019 Jan;51(1):117-127. PMID: 30578417.