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Heterozygous WNT1 variant causing a variable bone phenotype.

ABSTRACT: Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in WNT1 cause severe OI. Heterozygous missense variants in WNT1 are responsible for early-onset osteoporosis with variable bone phenotypes. Herein, we report a third-generation family with four affected individuals, some presenting with multiple low-impact fractures in childhood and others presenting with early-onset osteoporosis without a striking fracture history. A WNT1 variant (c. 1051 > C; p.Trp351Arg) was identified in the proband and segregated with a bone phenotype in three additional family members, consistent with autosomal dominant inheritance. In the proband, whole genome sequencing also revealed a de novo duplication (434 kb) of 22q11.2 that involves 25 genes, 4 of which are associated with human disease when haploinsufficient. Though smaller than the typical (1.5 Mb) 22q11.2 duplication, the duplication in the proband may be responsible for additional nonosseous aspects of his phenotype (hypotonia, developmental delay, small genitalia, strabismus, and depression in preadolescence). This case demonstrates the variability of bone phenotype conferred by a WNT1 variant and extends the spectrum of bone phenotypes associated with heterozygous WNT1 mutations.

SUBMITTER: Alhamdi S

PROVIDER: S-EPMC6289778 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Heterozygous WNT1 variant causing a variable bone phenotype.

Alhamdi Shatha S Lee Yi-Chien YC Chowdhury Shimul S Byers Peter H PH Gottschalk Michael M Taft Ryan J RJ Joeng Kyu Sang KS Lee Brendan H BH Bird Lynne M LM

American journal of medical genetics. Part A 20180924 11

Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in WNT1 cause severe OI. Heterozygous missense variants in WNT1 are responsible for early-onset osteoporosis with variable bone phenotypes. Herein, we report a third-generation family with four affected individuals, some presenting with multiple l ...[more]

PMID: 30246918

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Project description:ObjectivesMethylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated methylmalonic acidemia is one of the most common types of MMA and is caused by mutations in the gene encoding methyl-malonyl coenzyme A mutase (MMUT). In this study, we investigated the possible mechanisms underlying the symptoms of isolated MMA in a patient by molecular analysis.MethodsPCR amplification and Sanger sequencing analysis was performed to identify variants in the MMUT gene in the proband and his family. Furthermore, minigene constructs were generated to validate the splicing defects in the MMUT gene variant identified in the proband.ResultsThe 3-year-old patient was admitted to the hospital with symptoms of MMA, including fever, convulsions, and vomiting. He showed metabolic acidosis, high levels of methylmalonic acid in blood and urine, and normal blood homocysteine levels. Genetic analysis demonstrated that the patient was a compound heterozygous carrier of two variants in the MMUT gene: a missense c.278G > A variant that has already been reported in a patient with the severe mut⁰ phenotype; and a novel splice site variant c.2125-2A > G. RT-PCR analysis showed that, while the novel variant clearly alters splicing, a minor amount of a full-length transcript is generated, suggesting that a wild-type protein may be produced although at a lower quantitative level. The patient's condition improved after treatment with vitamin B12. Serious complications were not reported during follow-up at age 5.ConclusionsWe identified a novel splice site variant that partially disrupts normal splicing of the MMUT pre-mRNA. Production of a reduced amount of full-length transcript is responsible for the mild clinical phenotype observed in this patient. Functional studies have proven useful in exploring the genotype-phenotype association and in providing guidance for the genetic diagnosis of MMA.

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Heterozygous WNT1 variant causing a variable bone phenotype.

Publications

Heterozygous WNT1 variant causing a variable bone phenotype.

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