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

Abstract

Only a few individuals with 12q15 deletion have been described, presenting with a disorder characterized by learning disability, developmental delay, nasal speech, and hypothyroidism. The smallest region of overlap for this syndrome was included in a genomic segment spanning CNOT2, KCNMB4, and PTPRB genes. We report on an additional patient harboring a 12q15 microdeletion encompassing only part of CNOT2 gene, presenting with a spectrum of clinical features overlapping the 12q15 deletion syndrome phenotype. We propose CNOT2 as the phenocritical gene for 12q15 deletion syndrome and its haploinsufficiency being associated with an autosomal dominant disorder, presenting with developmental delay, hypotonia, feeding problems, learning difficulties, nasal speech, skeletal anomalies, and facial dysmorphisms. K E Y W O R D S 12q15, 12q deletion syndrome, CNOT2

CNOT2 haploinsufficiency causes a neurodevelopmental disorder with characteristic facial features

“…The phenotypes of the patient we have documented herein with a heterozygous nonsense variant in the CNOT2 gene itself and of three recently documented patients with a microdeletion in the chromosomal 12q15 region including the CNOT2 gene (Alesi et al, , ; Uehara et al, ) significantly overlap each other (Table ). The phenotypic spectrum of the newly recognized disorder consists of a language development delay and characteristic facial features including upslanted palpebral fissures, anteverted nares, a thin upper‐lip, and micrognathia.…”

“…CNOT2 had previously been reported to be one of the causative genes of major phenotypes of 12q15 microdeletion syndrome (Alesi et al, ). In 2019, after our article was published, Alesi et al reported a patient with syndromic intellectual disability and 85 kb intragenic deletion of CNOT2 (Alesi et al, ). This patient with intragenic deletion of CNOT2 was detected by chromosomal microarray analysis (Alesi et al, ).…”

“…In 2019, after our article was published, Alesi et al reported a patient with syndromic intellectual disability and 85 kb intragenic deletion of CNOT2 (Alesi et al, ). This patient with intragenic deletion of CNOT2 was detected by chromosomal microarray analysis (Alesi et al, ). Any reports of patients with truncating single nucleotide substitutions or small indels (i.e., nonsense variant or frameshift variant) of the CNOT2 gene would provide direct evidence that CNOT2 is the causative gene of a human neurodevelopmental disorder.…”

“…Note the synophrys, bushy eyebrow, hirsutism, long eyelashes, upslanting palpebral fissures, thin upper-lip, low-set ears, and micrognathia. The right panel shows the patient's hands at six years of age; note the short fifth finger and clinodactyly of the fifth finger on his hands [Color figure can be viewed at wileyonlinelibrary.com] microarray analysis (Alesi et al, 2019). Any reports of patients with truncating single nucleotide substitutions or small indels (i.e., nonsense variant or frameshift variant) of the CNOT2 gene would provide direct evidence that CNOT2 is the causative gene of a human neurodevelopmental disorder.…”

Integrating a Genome-Wide Association Study With Transcriptome Analyses to Identify Candidate Genes and Pathways for Feed Conversion Ratio in Yorkshire Pigs

“…CNOT2 is an important regulator for energy metabolism, cellular stress and fatty acid metabolism in the skeletal muscles. The heterozygous intragenic deletion of CNOT2 displayed disordered phenotypes of learning disability, developmental delay, and hypothyroidism [65,66]. TRHDE is an extracellular peptidase that specifically degrades the TRH to regulate appetite and metabolism [67,68].…”