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Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation.

ABSTRACT: BACKGROUND:Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18-year-old boy with a profound growth retardation (<3 SD) besides typical clinical features of GSDIII, whereby endocrinological studies were negative. METHODS AND RESULTS:Molecular analysis of AGL gene revealed the homozygous reported variant c.3903_3904insA. Since discordant results from segregation studies showed the carrier status in one parent only, SNP array and short tandem repeats analyses were performed, revealing a paternal disomy of chromosome 1 (UPD1). CONCLUSION:This study describes the first case of GSDIII resulting from UPD1. UPD can play an important role even in case of imprinted genes. DIRAS3 is a maternally imprinted tumor suppressor gene, located on chromosome 1p31, and implicated in growth and oncogenesis. It can be speculated that DIRAS3 overexpression might have a role in the severe short stature of our patient. The study emphasizes the importance of parental segregation analysis especially in patients with recessive conditions to look for specific genetic causes of disease and to estimate properly the risk of family recurrence.

SUBMITTER: Ponzi E

PROVIDER: S-EPMC6503021 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation.

Ponzi Emanuela E Alesi Viola V Lepri Francesca R FR Genovese Silvia S Loddo Sara S Mucciolo Mafalda M Novelli Antonio A Dionisi-Vici Carlo C Maiorana Arianna A

Molecular genetics & genomic medicine 20190327 5

<h4>Background</h4>Glycogen storage disease type III (GSDIII) is caused by mutations of AGL gene with debranching enzyme deficiency. Patients with GSDIII manifest fasting hypoglycemia, hepatomegaly, hepatopathy, myopathy, and cardiomyopathy. We report on an 18-year-old boy with a profound growth retardation (<3 SD) besides typical clinical features of GSDIII, whereby endocrinological studies were negative.<h4>Methods and results</h4>Molecular analysis of AGL gene revealed the homozygous reported ...[more]

PMID: 30916492

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Project description:Background:Uniparental disomy (UPD) is a rare condition in which a child inherits both copies of a chromosome or chromosome segment from one parent. Medical consequences of UPD may include abnormal imprinting, unmasking of genetic disease, and somatic mosaicism; alternatively, the condition may be clinically silent. We present a case of maternal UPD for chromosome 6, a rare condition previously reported less than 20 times. In our patient with a normal phenotype, the condition was discovered through abnormal paternity testing results. Uniparental isodisomy is a rare cause of discordant parentage testing results, but it is an important phenomenon to recognize. Case presentation:We present a female born at 32?weeks gestational age with birth weight 10-25%ile when corrected for prematurity. Paternity testing was obtained for legal reasons, and initial results appeared to exclude the alleged father. However, the lab performed additional testing which indicated that the patient was homozygous for maternal alleles for all three tested loci located on chromosome 6. Based on these results, the patient was referred for a medical genetics evaluation for possible maternal uniparental disomy. She presented for her consultation at 10?months of age and appeared to be developing appropriately. Her age-adjusted weight, length, and head circumference were <3%ile, 10%ile, and 25%ile respectively. Chromosomal microarray testing confirmed maternal UPD6. The patient was seen again at 14?months of age, and her weight and length were 10-25%ile. She had not developed concerning symptoms or physical exam findings. Conclusions:The presence of UPD, especially in asymptomatic patients, has implications for paternity testing, as standard methods may miss cases of both isodisomy and heterodisomy. This rare inheritance pattern should be considered when discordant paternity results come under suspicion. It is unusual for a parentage testing lab to perform the amount of testing done for this case, but the initial inconsistencies necessitated further investigation. UPD6 has uncertain effects and variable phenotypes, so this patient's genetic abnormality likely would have gone undiscovered if not for the non-medical indication for the laboratory analysis. Her asymptomatic presentation raises the possibility that UPD may be more common than previously estimated.

Project description:LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.

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Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation.

Publications

Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation.

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