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Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant

A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG-related disorders. We reported a 4-month-o...

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Autores principales: Sriwattanapong, Kanokwan, Rojnueangnit, Kitiwan, Theerapanon, Thanakorn, Srichomthong, Chalurmpon, Porntaveetus, Thantrira, Shotelersuk, Vorasuk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930966/
https://www.ncbi.nlm.nih.gov/pubmed/33562887
http://dx.doi.org/10.3390/ijns7010009
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author Sriwattanapong, Kanokwan
Rojnueangnit, Kitiwan
Theerapanon, Thanakorn
Srichomthong, Chalurmpon
Porntaveetus, Thantrira
Shotelersuk, Vorasuk
author_facet Sriwattanapong, Kanokwan
Rojnueangnit, Kitiwan
Theerapanon, Thanakorn
Srichomthong, Chalurmpon
Porntaveetus, Thantrira
Shotelersuk, Vorasuk
author_sort Sriwattanapong, Kanokwan
collection PubMed
description A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG-related disorders. We reported a 4-month-old infant who presented with developmental delay, fever, and diarrhea. Within two weeks after hospital admission, the patient developed hepatic failure and died. Liver necropsy demonstrated an extensive loss of hepatocytes and bile duct proliferations. Trio-whole exome sequencing identified that the patient was compound heterozygous for a novel frameshift variant c.3102delG (p.Lys1035Serfs*59) and a common variant c.3286C>T (p.Arg1096Cys) in POLG (NM_002693.3) inherited from the mother and father, respectively. The c.3102delG (p.Lys1035Serfs*59) was a null variant and classified as pathogenic according to the American College of Medical Genetics and Genomics Standards and Guidelines. Prenatal genetic screenings using rapid whole exome sequencing successfully detected the heterozygous c.3286C>T variant in the following pregnancy and the normal alleles in the other one. Both children had been healthy. We reviewed all 34 cases identified with the POLG c.3286C>T variant and found that all 15 compound heterozygous cases had two missense variants except our patient who had the truncating variant and showed the earliest disease onset, rapid deterioration, and the youngest death. All homozygous cases had disease onset before age 2 and developed seizure. Here, we report a novel POLG variant expanding the genotypic spectrum, demonstrate the successful use of exome sequencing for prenatal and neonatal screenings of POLG-related disorders, and show the genotype–phenotype correlation of the common c.3286C>T variant.
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spelling pubmed-79309662021-03-05 Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant Sriwattanapong, Kanokwan Rojnueangnit, Kitiwan Theerapanon, Thanakorn Srichomthong, Chalurmpon Porntaveetus, Thantrira Shotelersuk, Vorasuk Int J Neonatal Screen Case Report A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG-related disorders. We reported a 4-month-old infant who presented with developmental delay, fever, and diarrhea. Within two weeks after hospital admission, the patient developed hepatic failure and died. Liver necropsy demonstrated an extensive loss of hepatocytes and bile duct proliferations. Trio-whole exome sequencing identified that the patient was compound heterozygous for a novel frameshift variant c.3102delG (p.Lys1035Serfs*59) and a common variant c.3286C>T (p.Arg1096Cys) in POLG (NM_002693.3) inherited from the mother and father, respectively. The c.3102delG (p.Lys1035Serfs*59) was a null variant and classified as pathogenic according to the American College of Medical Genetics and Genomics Standards and Guidelines. Prenatal genetic screenings using rapid whole exome sequencing successfully detected the heterozygous c.3286C>T variant in the following pregnancy and the normal alleles in the other one. Both children had been healthy. We reviewed all 34 cases identified with the POLG c.3286C>T variant and found that all 15 compound heterozygous cases had two missense variants except our patient who had the truncating variant and showed the earliest disease onset, rapid deterioration, and the youngest death. All homozygous cases had disease onset before age 2 and developed seizure. Here, we report a novel POLG variant expanding the genotypic spectrum, demonstrate the successful use of exome sequencing for prenatal and neonatal screenings of POLG-related disorders, and show the genotype–phenotype correlation of the common c.3286C>T variant. MDPI 2021-02-05 /pmc/articles/PMC7930966/ /pubmed/33562887 http://dx.doi.org/10.3390/ijns7010009 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Sriwattanapong, Kanokwan
Rojnueangnit, Kitiwan
Theerapanon, Thanakorn
Srichomthong, Chalurmpon
Porntaveetus, Thantrira
Shotelersuk, Vorasuk
Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
title Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
title_full Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
title_fullStr Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
title_full_unstemmed Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
title_short Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant
title_sort compound heterozygosity for a novel frameshift variant causing fatal infantile liver failure and genotype–phenotype correlation of polg c.3286c>t variant
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930966/
https://www.ncbi.nlm.nih.gov/pubmed/33562887
http://dx.doi.org/10.3390/ijns7010009
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