Inherited cases of CNOT3‐associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies

Abstract

De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.

Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype

“…By reviewing the clinical features associated with pathogenic CNOT3 and SMAD6 variants, we suspected a causal role of CNOT3 haploinsufficiency in the pathogenesis of the peculiar facial features, ID and behavioral anomalies, based on two recently published papers reporting 16 sporadic cases and two families with multiple affected members sharing pathogenic variants in this gene [ 11 , 12 ]. On the other hand, we could ascribe the severe congenital heart defect to the heterozygous truncating variant in SMAD6 .…”

“…We reviewed the available published clinical data of IDDSADF to assess consistent dysmorphic features and clinical signs ( Table 1 ). Although previously reports of patients affected with this disorder failed to recognize an obvious facial gestalt [ 11 , 12 ], common dysmorphisms are undoubtedly present. Blind evaluation of the clinical pictures and descriptions of affected individuals by three experienced clinical geneticists evidenced some recurrent facial findings.…”

“…A broad nasal tip (11/21, 52%) with anteverted nares (11/16, 69%) is also a common finding, together with a smooth (11/18, 61%), long philtrum (8/18, 44%) and thin upper lip (11/18, 61%). Prominence of the lower lip with increase of labiomental groove was noted in 75% of patients (9/12) for whom a published clinical picture was available (pts 1/3/4/9/12/14/16 from Martin and colleagues [ 11 ]; pts II:3 and III:1 family 1 from Meyer and colleagues [ 12 ]). The facial gestalt of the disorder, as described above, is recapitulated well by our proband.…”

“…The facial gestalt of the disorder, as described above, is recapitulated well by our proband. Previous reports [ 11 , 12 ] evidenced some additional features (i.e. : low-set eyebrows [ 11 ] and triangular face with small chin [ 12 ]) in a subset of patients.…”

“…Heterozygous variants in CNOT3 , encoding a subunit of the CCR4-NOT protein complex, a multimeric regulator with variegated function in mRNA metabolism and gene expression, have recently been reported to cause a developmental delay (DD)/intellectual disability (ID) condition ( i ntellectual d evelopmental d isorder with s peech delay, a utism, and d ysmorphic f acies (IDDSADF), Mendelian Inheritance in Man (MIM): 618672) [ 10 , 11 , 12 ]. CNOT3 variants are largely truncating, which supports haploinsufficiency as the mechanism of disease.…”