ClinVar Genomic variation as it relates to human health

The copy number loss of 1q25.2q31.1 involves several coding genes across multiple chromosomal bands and is expected to cause phenotypic and/or developmental abnormalities. It includes multiple genes associated with autosomal dominant disorders: LHX4 (OMIM 602146), XPR1 (OMIM 605237), CACNA1E (OMIM 601013), RNASEL (OMIM 180435), IVNS1ABP (OMIM 609209), and HMCN1 (OMIM 608548). This deletion interval overlaps the region of intermediate 1q25-q32 deletion syndrome, which is characterized by pre- and/or postnatal growth retardation, psychomotor retardation, lip and palate anomalies, genital abnormalities, terminal limb defects, cardiac anomalies, microcephaly, and dysmorphic features. The severity of the clinical phenotype seems to be correlated with the size of the deletion (Hu et al., Mol Cytogenet 2013;6(1):30, PMID: 23915434). CENPL (not encompassed in this deletion interval) and LHX4 have been suggested as the strongest candidates for growth retardation in the 1q25-q32 region; however, there were several discordant reports regarding LHX4 deletion and growth deficiency (Burkardt et al., Am J Med Genet A 2011;155A(6):1336-51, PMID: 21548129; Filges et al., Pediatrics 2012;129(2):e529-34, PMID: 22232309). Haploinsufficiency of LHX4 is associated with autosomal dominant combined pituitary hormone deficiency-4 (OMIM 262700), which causes growth deficiency due to impaired production of growth hormone and one or more anterior pituitary hormones. Based on genotype-phenotype analysis, a 3.1 Mb critical region has been proposed for the intellectual disability phenotype at 1q25.2, which contains 24 genes, including seven OMIM genes (ASTN1, RASAL2, ANGPTL1, FAM20B, TOR3A, ABL2, and SOAT1). Many of these genes are encompassed in this deletion interval (Hu et al., Mol Cytogenet 2013;6(1):30, PMID: 23915434).