TMCO1 – Cerebrofaciothoracic Dysplasia

Cerebrofaciothoracic dysplasia (CFTD) is an autosomal recessive multiple congenital anomaly syndrome characterized by macrocrania at birth, brachycephaly, hypoplasia of the corpus callosum, flat facies, hypertelorism, cleft lip/palate, short neck, and skeletal anomalies, all accompanied by severe intellectual disability.

Homozygosity mapping in four consanguineous Turkish families identified a founder homozygous nonsense mutation, c.259C>T (p.Arg87Ter), in TMCO1, implicating loss-of-function alleles in CFTD pathogenesis (PMID:24194475). Exclusion of this locus in a fifth family provided evidence for genetic heterogeneity within the CFTD spectrum.

Subsequent case series reported four additional patients—three affected brothers and one unrelated individual—from Pakistani and Scottish backgrounds sharing a recurrent homozygous c.292_293del (p.Ser98Ter), expanding the disorder beyond the Amish and Turkish founder populations (PMID:30556256).

A decade-long review consolidated these findings, detailing 27 molecularly confirmed patients with biallelic TMCO1 loss-of-function variants across diverse ethnicities, including nonsense, frameshift, and splice-site mutations, with recurrent founder alleles in Amish (c.292_293del) and Turkish (c.259C>T) cohorts (PMID:34093650).

Segregation analyses in multiple pedigrees confirmed autosomal recessive inheritance, with homozygous TMCO1 variants co-segregating with the phenotype in multiplex sibships (three affected siblings) and consanguineous families (PMID:30556256).

Functional studies established TMCO1 as an endoplasmic reticulum Ca2+ leak channel essential for preventing ER Ca2+ overload. Loss-of-function disrupts Ca2+ homeostasis in patient-derived cells, and restoration of TMCO1 expression normalizes ER Ca2+ levels, supporting a haploinsufficiency mechanism (PMID:34093650).

Advanced neuroimaging in two additional patients revealed novel features—hippocampal malrotation and pontine hypoplasia—further broadening the neurodevelopmental spectrum of TMCO1 deficiency (PMID:36451910).

In summary, there is robust evidence that biallelic TMCO1 loss-of-function mutations cause autosomal recessive CFTD, with consistent craniofacial, skeletal, and neurodevelopmental manifestations. TMCO1 sequencing is recommended in diagnostic workflows for intellectual disability syndromes with characteristic craniofacial dysmorphism.

References

• American Journal of Human Genetics • 2013 • Homozygosity mapping identifies TMCO1 mutations in Turkish families with cerebrofaciothoracic dysplasia PMID:24194475
• American Journal of Medical Genetics Part A • 2019 • Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant PMID:30556256
• Frontiers in Genetics • 2021 • From Disease Description and Gene Discovery to Functional Cell Pathway: A Decade-Long Journey for TMCO1 PMID:34093650
• BJR Case Reports • 2022 • Brain and spine MRI findings in children presenting with TMCO1 mutation PMID:36451910

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