Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 in two new patients with the same homozygous TMCO1 variant and review of the literature

Eur J Med Genet. 2023 Mar;66(3):104715. doi: 10.1016/j.ejmg.2023.104715. Epub 2023 Jan 25.


Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1; OMIM#213980) is a rare autosomal recessive disorder characterized by the clinical triad of developmental delay and/or intellectual disability, a typical facial gestalt with brachycephaly, highly-arched bushy eyebrows, synophrys, hypertelorism, wide nasal bridge, and short nose, as well as multiple vertebrae and rib malformations, such as bifid and fused ribs and abnormal vertebral segmentation and fusion. Biallelic loss-of-function variants in TMCO1 cause CFSMR1. We report on two unrelated Egyptian patients with a phenotype suggestive of CFSMR. Single whole-exome sequencing in patient 1 and Sanger sequencing of TMCO1 in patient 2 revealed the same homozygous TMCO1 nonsense variant c.187C > T/p.(Arg63*) in both affected individuals; patients' healthy parents were heterozygous carriers of the variant. Congenital hearing loss in patients 1 and 2 is an occasional finding in individuals affected by CFSMR. Camptodactyly and syndactyly, which were noted in patient 2, have not or rarely been reported in CFSMR. Review of the literature revealed a total of 30 individuals with the clinically recognizable and unique phenotype of CFSMR1, including the patients reported here, who all carried biallelic TMCO1 variants. Six different TMCO1 variants have been reported in the 30 patients from 14 families, comprising three nonsense, two 2-bp deletions, and a splice donor site variant. All disease-associated TMCO1 variants likely represent null alleles resulting in absence of the encoded protein. TMCO1 has been proposed to act as a Ca2+ channel, while other data revealed TMCO1 as a mitochondrial protein and a component of the translocon at the endoplasmic reticulum, a cellular machinery important for the biogenesis of multi-pass membrane proteins. RAB5IF/C20orf24 has recently been identified as causative gene for craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2; OMIM#616994). Heterodimerization of RAB5IF/C20orf24 and TMCO1 and their interdependence may suggest a pathophysiological role of ER-mitochondria interaction underlying CFSMR.

Keywords: Cerebro-facio-thoracic dysplasia; Craniofacial dysmorphism; Mitochondria; Skeletal anomalies; TMCO1; TMCO1 defect syndrome; Uniparental disomy.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Abnormalities, Multiple* / genetics
  • Calcium Channels / genetics
  • Craniofacial Abnormalities* / genetics
  • Humans
  • Intellectual Disability* / genetics
  • Musculoskeletal Abnormalities* / genetics
  • Phenotype


  • Calcium Channels
  • TMCO1 protein, human

Supplementary concepts

  • Cerebrofaciothoracic Dysplasia