From Disease Description and Gene Discovery to Functional Cell Pathway: A Decade-Long Journey for TMCO1

A decade has passed since transmembrane coiled-coil domains 1 (TMCO1) defect syndrome was identified in 11 undiagnosed patients within the Old Order Amish of Northeastern Ohio—a disorder characterized by a distinctive craniofacial dysmorphism, skeletal anomalies and global developmental delay. Twenty seven patients, from diverse ethnic groups, have been reported with pathogenic TMCO1 variants now recognized to cause cerebrofaciothoracic dysplasia (CFTD). The implication of previously uncharacterized TMCO1 within disease has instigated a 10-year journey to understand the function of TMCO1 protein in Ca2+ homeostasis. TMCO1 is an ER Ca2+ leak channel which facilitates Ca2+ leak upon ER “overload” through the novel Ca2+ load activated Ca2+ mechanism. This mini-review brings together the clinical and scientific advances made since the discovery of TMCO1 deficiency in disease, including broadened phenotype, understanding of pathophysiology, and implications to patient management of TMCO1 defect syndrome.

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1q44 microdeletion syndrome: A new case with potential additional features

Romanian Journal of Medical Practice ◽

10.37897/rjmp.2021.1.16 ◽

2021 ◽

Vol 16 (1) ◽

pp. 92-96

Author(s):

Elena-Silvia SHELBY ◽

◽

Tanser HUSEYINOGLU ◽

Georgeta CARDOS ◽

Liliana PADURE ◽

...

Keyword(s):

Developmental Delay ◽

Grey Matter ◽

Chromosome 1 ◽

Global Developmental Delay ◽

Microdeletion Syndrome ◽

Genetic Syndrome ◽

Skeletal Involvement ◽

Craniofacial Dysmorphism ◽

Prenatal Hydronephrosis ◽

One Year

1q44 microdeletion syndrome (1q44 monosomy) is a newly described genetic syndrome characterized by the haploinsufficiency of a 6 Mb locus on the long arm of chromosome 1. The main features are global developmental delay, seizures, hypotonia and craniofacial dysmorphism. With a prevalence below one in a million cases, this syndrome is very rare and, hence, often passes undiagnosed. We present the case of a one year old girl admitted to our hospital with global developmental delay and several congenital abnormalities suggesting a plurimalformative syndrome. Microarray analysis detected a 967 kb deletion in the 1q44 region as well as a a 530 kb microduplication in the 14q31.1q31.2 region, the latter having unknown clinical significance as it contains no currently known OMIM genes. The patient’s phenotype was in accordance to 1q44 microdeletion syndrome. Furthermore, after studying the 1q44 microdeletion syndrome cases reported so far in the literature, we have noticed that our patient presented previously undescribed features of this syndrome, namely prenatal hydronephrosis, bifid hallux and grey matter heterotopy. Based on the cerebral, renal and skeletal involvement in 1q44 microdeletion syndrome, we suspect these might be additional, previously unreported features of 1q44 microdeletion syndrome.

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A de novo Pericentric Inversion in Chromosome 4 Associated with Disruption of PITX2 and a Microdeletion in 4p15.2 in a Patient with Axenfeld-Rieger Syndrome and Developmental Delay

Cytogenetic and Genome Research ◽

10.1159/000456695 ◽

2017 ◽

Vol 151 (1) ◽

pp. 5-9 ◽

Cited By ~ 2

Author(s):

Živilė Maldžienė ◽

Eglė Preikšaitienė ◽

Salomėja Ignotienė ◽

Natalija Kapitanova ◽

Algirdas Utkus ◽

...

Keyword(s):

Developmental Delay ◽

Pericentric Inversion ◽

Patient Management ◽

De Novo ◽

Chromosomal Rearrangements ◽

Genetic Alterations ◽

Chromosome 4 ◽

Rieger Syndrome ◽

Craniofacial Dysmorphism ◽

The Family

Axenfeld-Rieger syndrome (ARS) is a clinically and genetically heterogeneous group of autosomal dominantly inherited malformations that predominantly affect the eye but are also associated with craniofacial dysmorphism and dental abnormalities. A broad spectrum of genetic alterations involving PITX2 and FOXC1 lead to ARS. We report on a 4-year-old girl with clinical features of ARS and developmental delay due to a de novo apparently balanced pericentric inversion in chromosome 4. This report emphasizes that complementary investigations are necessary to precisely characterize chromosomal rearrangements. Elucidation of the exact genetic cause of ARS is important for comprehensive genetic counseling of the family members and for better patient management.

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