Nasal speech and hypothyroidism are common hallmarks of 12q15 microdeletions

Abstract

The introduction of array CGH in clinical diagnostics has led to the discovery of many new microdeletion/microduplication syndromes. Most of them are rare and often present with a variable range of clinical anomalies. In this study we report three patients with a de novo overlapping microdeletion of chromosome bands 12q15q21.1. The deletions are similar to 2.5Mb in size, with a 1.34-Mb common deleted region containing six RefSeq genes. All three patients present with learning disability or developmental delay, nasal speech and hypothyroidism. In this paper we will further elaborate on the genotype-phenotype correlation associated with this deletion and compare our patients with previously reported cases

CNOT2 as the critical gene for phenotypes of 12q15 microdeletion syndrome

“…We demonstrated herein that CNOT2 , a gene encoding a component of the carbon catabolite repressor 4 (CCR4)‐negative on TATA (NOT) complex, represents the only known “loss‐of‐function intolerant” gene (Lek et al, ) that was commonly deleted among the 12‐year‐old female patient documented herein and all the 16 previously reported patients (Alesi et al, ; Firth et al, ; Lopez et al, ; Schluth et al, ; Vergult et al, ) (Figure ). Thus, we suggest that CNOT2 is the candidate gene for the commonly shared phenotypes of 12q15 microdeletion syndrome among these patients, including intellectual disability, nasal speech, upslanting and short palpebral fissures, and micrognathia.…”

“…Chromosome 12q15 microdeletion syndrome is a rare disease characterized by intellectual disability, a nasal voice, and dysmorphic facial features, including upslanting palpebral fissures, low‐set ears, and micrognathia. To date, 16 patients with chromosome 12q15 microdeletion have been reported or registered in the DECIPHER database (Alesi et al, ; Firth et al, ; Lopez et al, ; Schluth et al, ; Vergult et al, ). Little is known about the associations between each of the deleted genes and the phenotypes of the 12q15 microdeletion syndrome.…”

Search for a gene responsible for Floating‐Harbor syndrome on chromosome 12q15q21.1

“… Array‐CGH profile of chromosome 12 showing deletion of the 12q15q21.1 region with genes deleted in the region of interest in our proposita (hg18, Patient 1), as well as the locations of the pure overlapping deletions of <10 Mb reported in the literature (black bars with decipher numbers, [Vergult et al, 2011]) or unpublished gathered via the Decipher network (hg18, grey bars, Decipher 253254). …”

A heterozygous, intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome

“…deletions range in size from 25.5 Mb (Klein et al, 2005) to 742 kb (Alesi et al, 2017). Although the critical SRO has been restricted to 12q15 (Alesi et al, 2017;Vergult et al, 2011), the exact contribution of candidate genes to the phenotype has not been yet established.…”

“…Standard and molecular-cytogenetic techniques disclosed a common deleted region spanning from 12q15-12q21.1 to 12q21.33. Schluth et al (2008) reported a 7.7-10 Mb deletion in 12q15q21.2 in a patient presenting with clinical features superimposable to those described in the first patients, while Vergult et al (2011), based on the genomic analysis of three other subjects, further refined the smallest region of overlap (SRO) at 12q15. This region spans 1.34 Mb of genomic DNA and includes 6 RefSeq genes, CNOT2, KCNMB4, PTPRB, PTPRR, TSPAN8, and LGR5, which have been considered responsible for a disorder characterized by learning disability, developmental delay, nasal speech, and hypothyroidism.…”