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

Abstract

Chromosome 12q15 microdeletion syndrome is characterized by intellectual disability and dysmorphic facial features, but the associations between each of the deleted genes and the phenotypes of 12q15 microdeletion syndrome remain unclear. Recently, the smallest region of overlap in 16 previously reported patients was used to define three candidate genes for the 12q15 microdeletion syndrome: CNOT2, KCNMB4, and PTPRB. Among these three candidate genes, CNOT2 maintains the structural integrity of the carbon catabolite repressor 4 (CCR4)‐negative on TATA (NOT) complex, which plays a key role in regulating global gene expression, and is essential for the enzymatic activity of the CCR4‐NOT complex. Disruption of the CCR4‐NOT complex results in dysregulation of global gene expression, and is associated with various human disease processes, including neuronal diseases. Therefore, CNOT2 haploinsufficiency might account for the neurological features of the 12q15 microdeletion syndrome. Herein, we document a 12‐year‐old female patient with mild intellectual disability and multiple structural abnormalities including cleft lip and palate and 2–3 toe syndactyly. She exhibited dysmorphic facial features such as upslanting and short palpebral fissures, micrognathia, low‐set ears, and hypoplastic antihelix. A microarray analysis showed a de novo 1.32‐Mb deletion within 12q15 that included CNOT2 and 14 other genes. Remapping of the 12q15 deletion region in the 16 previously reported patients together with that in the newly identified patient indicated that CNOT2 is the only gene that is commonly deleted. These findings suggest that CNOT2 is the prime candidate for the neurological phenotypes of the 12q15 microdeletion syndrome.

De novocoding variants in theAGO1gene cause a neurodevelopmental disorder with intellectual disability

“…In the developing mouse brain, although it is ubiquitously expressed, Ago1 was shown to be upregulated in neurogenic progenitors and mature neurons 37 . This expression pattern correlates with initial findings showing a role for human AGO1 in promoting differentiation after neuronal induction in a cellular model of neuroblastoma SH-SY-5Y cells 37 CNOT2 39 , CNOT3 40 or DDX6 41 , have been reported to cause NDDs 42 . Apart from their role in post-transcriptional regulation, human AGO1 and AGO2 proteins are also involved in the regulation of transcription and splicing 9 .…”

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.…”

“…Since macrocephaly was present only in the patient with the CNOT2 mutation, it remains unclear whether macrocephaly is a characteristic phenotype. The motor delay in the two patients described above with a 12q15 microdeletion including a CNOT2 deletion and the patient documented in this article with CNOT2 truncating variant were mild (Alesi et al, ; Uehara et al, ).…”

“…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, 2017(Alesi et al, , 2019Uehara et al, 2019) significantly overlap each other ( Table 1). (Alesi et al, 2017;Uehara et al, 2019).…”

“…We recently reported a female patient with intellectual disability, characteristic facial features, and 1.32‐Mb microdeletion within chromosome 12q15 (Uehara et al, ). In the article, we concluded that the haploinsufficiency of CNOT2 may explain at least some, if not all, of the core clinical features of patients with 12q15 microdeletion syndrome.…”