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Segmental uniparental disomy of chromosome 4 in a patient with methylmalonic acidemia.

ABSTRACT: BACKGROUND:Methylmalonic acidemia (MMA) is an autosomal recessive genetic disorder involving the metabolism of organic acids. METHODS:Here, we report the case of a patient who developed acute metabolic crisis after vaccination and was diagnosed with cblA type MMA after hospitalization. RESULTS:Further examination revealed a homozygous pathogenic variant in the MMAA gene that caused the disease in the patient but did not conform to Mendelian inheritance. Using chromosomal microarray analysis, maternal uniparental disomy (UPD) was found on chromosome 4q26-q35.2 of the patient. The MMAA gene of the patient was inherited only from the mother and carried the same pathogenic variant on both alleles of chromosome 4. MMAA gene expression levels in whole blood were detected by real-time PCR. CONCLUSION:The nonsense pathogenic variant, NM_172250.2:c.742C>T (p.Gln248*), carried by the patient leads to a premature termination of transcription of the gene, thereby resulting in partial loss of protein function while retaining some others. Segmental UPD 4 is rare, and to our knowledge, has not been reported previously.

SUBMITTER: Chen M

PROVIDER: S-EPMC6978399 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Segmental uniparental disomy of chromosome 4 in a patient with methylmalonic acidemia.

Chen Min M Hao Hu H Xiong Hui H Cai Yao Y Ma Fei F Shi Congcong C Xiao Xin X Li Sitao S

Molecular genetics & genomic medicine 20191202 1

<h4>Background</h4>Methylmalonic acidemia (MMA) is an autosomal recessive genetic disorder involving the metabolism of organic acids.<h4>Methods</h4>Here, we report the case of a patient who developed acute metabolic crisis after vaccination and was diagnosed with cblA type MMA after hospitalization.<h4>Results</h4>Further examination revealed a homozygous pathogenic variant in the MMAA gene that caused the disease in the patient but did not conform to Mendelian inheritance. Using chromosomal mi ...[more]

PMID: 31793236

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Project description:OBJECTIVE: To review all cases with segmental and/or complex uniparental disomy (UPD), to study aetiology and mechanisms of formation, and to draw conclusions. DESIGN: Searching published reports in Medline. RESULTS: The survey found at least nine cases with segmental UPD and a normal karyotype, 22 cases with UPD of a whole chromosome and a simple or a non-homologous Robertsonian translocation, eight cases with UPD and two isochromosomes, one of the short arm and one of the long arm of a non-acrocentric chromosome, 39 cases with UPD and an isochromosome of the long arm of two homologous acrocentric chromosomes, one case of UPD and an isochromosome 8 associated with a homozygous del(8)(p23.3pter), and 21 cases with UPD of a whole or parts of a chromosome associated with a complex karyotype. Segmental UPD is formed by somatic recombination (isodisomy) or by trisomy rescue. In the latter mechanism, a meiosis I error is associated with meiotic recombination and an additional somatic exchange between two non-uniparental chromatids. Subsequently, the chromatid that originated from the disomic gamete is lost (iso- and heterodisomy). In cases of UPD associated with one isochromosome of the short arm and one isochromosome of the long arm of a non-acrocentric chromosome and in cases of UPD associated with a true isochromosome of an acrocentric chromosome, mitotic complementation is assumed. This term describes the formation by misdivision at the centromere during an early mitosis of a monosomic zygote. In cases of UPD associated with an additional marker chromosome, either mitotic formation of the marker chromosome in a trisomic zygote or fertilisation of a gamete with a marker chromosome formed in meiosis by a disomic gamete or by a normal gamete and subsequent duplication are possible. CONCLUSIONS: Research in the field of segmental and/or complex UPD may help to explain undiagnosed non-Mendelian disorders, to recognise hotspots for meiotic and mitotic recombinations, and to show that chromosomal segregation is more complex than previously thought. It may also be helpful to map autosomal recessively inherited genes, genes/regions of genomic imprinting, and dysmorphic phenotypes. Last but not least it would improve genetic counselling.

Dataset Information

Segmental uniparental disomy of chromosome 4 in a patient with methylmalonic acidemia.

Publications

Segmental uniparental disomy of chromosome 4 in a patient with methylmalonic acidemia.

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