1p36 deletion syndrome: an update

Abstract

Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes.

Genotype-phenotype correlations in individuals with pathogenicREREvariants

“…Many of the features seen in RERE-deficient mice overlap those associated with 1p36 deletion syndrome (MIM# 607872) in humans, which is characterized by developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies (Jordan, Zaveri, & Scott, 2015;Kang et al, 2007;Shapira et al, 1997). Since RERE is located within the proximal 1p36 deletion syndrome critical region, Kim et al (2013) hypothesized that RERE haploinsufficiency in humans is likely to contribute to many of the phenotypes seen in individuals with terminal and interstitial 1p36 deletions that include RERE (Jordan et al, 2015). This hypothesis was supported by Fregeau et al (2016) who identified 10 individuals with intellectual disability, developmental delay and/or autism spectrum disorder that carried rare, heterozygous putatively damaging sequence variants in RERE.…”

Screening for Subtelomeric Rearrangements in Thai Patients with Intellectual Disabilities Using FISH and Review of Literature on Subtelomeric FISH in 15,591 Cases with Intellectual Disabilities

“…Both syndromes have overlapping clinical features, including growth retardation, variable degree of ID/developmental delay, structural brain abnormalities, hypotonia, seizures, skeletal abnormalities, congenital heart defects, and hearing loss [38–40]. However, they are clinically recognized by distinct facial features, such as a Greek warrior helmet appearance of the nose, along with prominent glabella in the 4p deletion syndrome, and straight eyebrows, deeply set eyes, and midface retrusion in the 1p36 deletion syndrome.…”

The Nucleome of Developing Murine Rod Photoreceptors

“…1A-C and S1). The region contains the Icmt gene encoding isoprenylcysteine carboxyl methyltransferase, which is required for photoreceptor function 15 , the Kcnab2 gene encoding a potassium voltage-gated channel that is lost in 1p36deletion syndrome 16,17 , and the Rnf207 gene encoding a ring finger protein that is expressed only in 11-month-old mouse retinae (Figs. 1A and S1A,B).…”