title: Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A.
abstract: Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (p.M400I) and MAN1B1 c.1000C>T (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in SEC23A only. Mutations in SEC23A are responsible for craniolenticosultura dysplasia (CLSD). CLSD patients are short, have late-closing fontanels, and have reduced procollagen (pro-COL1A1) secretion because of abnormal pro-COL1A1 retention in the endoplasmic reticulum (ER). The mutation we identified in MAN1B1 was previously associated with reduced MAN1B1 protein and congenital disorders of glycosylation (CDG). CDG patients are also short, are obese, and have abnormal glycan remodeling. Molecular analysis of fibroblasts from the family revealed normal levels of SEC23A in all cells and reduced levels of MAN1B1 in cells with heterozygous or homozygous mutations in SEC23A and MAN1B1. Secretion of pro-COL1A1 was increased in fibroblasts from the siblings and patients, and pro-COL1A1 was retained in Golgi of heterozygous and homozygous mutant cells, although intracellular pro-COL1A1 was increased in patient fibroblasts only. We postulate that increased pro-COL1A1 secretion is responsible for tall stature in these patients and an unaffected sibling, and not previously discovered in patients with mutations in either SEC23A or MAN1B1. The patients in this study share biochemical and cellular characteristics consistent with mutations in MAN1B1 and SEC23A, indicating a digenic disease.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada;
authors.forename: Swati
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada;
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada;
authors.forename: Tracy
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada;
authors.forename: Laura
authors.initials: L
authors.lastname: Dempsey Nunez
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada;; Department of Pediatrics, McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.affiliation: Department of Medical Genetics, Child and Family Research Institute, Vancouver, British Columbia V6H 3V4, Canada;
authors.forename: William T
authors.initials: WT
authors.lastname: Gibson
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: Brian
authors.initials: B
authors.lastname: Gilfix
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada;
authors.forename: John J M
authors.initials: JJ
authors.lastname: Bergeron
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada;; Department of Pediatrics, McGill University, Montreal, Quebec H4A 3J1, Canada;; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.
authors.forename: Loydie A
authors.initials: LA
authors.lastname: Jerome-Majewska
keywords: childhood-onset truncal obesity; downslanted palpebral fissures; hypertelorism; macrocephaly at birth; moderate global developmental delay; proportionate tall stature