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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.

ABSTRACT: 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.

SUBMITTER: Sriwattanapong K

PROVIDER: S-EPMC7930966 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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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.

Sriwattanapong Kanokwan K Rojnueangnit Kitiwan K Theerapanon Thanakorn T Srichomthong Chalurmpon C Porntaveetus Thantrira T Shotelersuk Vorasuk V

International journal of neonatal screening 20210205 1

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 demonstra ...[more]

PMID: 33562887

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Project description:BackgroundFatal infantile hypertonic myofibrillar myopathy (FIHMM) is an autosomal recessive hereditary disease characterized by amyotrophy, progressive flexion contracture and ankylosis of the trunk and limb muscles, apnea and respiratory failure, and increased creatine phosphate levels. It is caused by mutations in the CRYAB gene, and only around 18 cases including genetic mutations have been reported worldwide. All patients with FIHMM develop respiratory distress, progressive stiffness of the limbs, and have a poor prognosis. However, no effective treatment for CRYAB-associated respiratory failure has been reported. Here, we report a case of FIHMM with a novel heterozygous missense mutation.Case presentationA 2-year-old female developed scoliosis of the lumbar spine and restrictive ventilatory dysfunction in infancy. She was admitted to the hospital with labored breathing on the third day after the second injection of inactivated poliomyelitis vaccine. Acute respiratory failure, pneumothorax, and cardiac arrest arose in the patient during hospitalization, and progressive stiffness of the trunk and limb muscles appeared, accompanied by obvious abdominal distension and an increase in phosphocreatine kinase levels. Screenings for genetic metabolic diseases in the blood and urine were normal. Electromyography revealed mild myogenic damage. A muscle biopsy indicated the accumulation of desmin, α-crystallin, and myotilin in the musculus biceps brachii, and dense granules were observed in muscle fibers using electron microscopy. Mutation analysis of CRYAB revealed a novel heterozygous missense mutation in the proband, c.302A > C (p.His101Pro) and c.3G > A (p.Met1Ile), which inherited from her asymptomatic, heterozygous carrier parents, respectively. The proband was finally diagnosed as FIHMM. One month after the FIHMM diagnosis, the child died of respiratory failure.ConclusionWe report a case of FIHMM with a novel heterozygous missense mutation of CRYAB. This finding might improve our understanding of FIHMM and highlight a novel mutation in the Chinese population.

Dataset Information

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

Publications

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

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