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Case Report: Complete Maternal Uniparental Isodisomy of Chromosome 5 (iUPD(5)mat) With PCSK1 Nonsense Variant in an Infant With Recurrent Diarrhea.

ABSTRACT: Congenital diarrhea diseases are a heterogeneous group of conditions and are the major cause of neonatal mortality worldwide. Proprotein convertase 1/3 (PC1/3) deficiency has been associated with severe malabsorptive diarrhea, obesity, and certain endocrine abnormalities. We report an infant born to non-consanguineous parents who is diagnosed with PC1/3 deficiency due to nonsense homozygous variant (c.238 C>T, p.Arg80Ter) in the PCSK1 gene, identified by Trio-exome sequencing (Trio-ES). The baby girl presented with recurrent diarrhea, transient liver dysfunction and hypoglycemia. Trio-ES showed complete maternal uniparental isodisomy (iUPD) of chromosome 5. Our finding provides accurate genetic counseling to this family and expands the clinical spectrum of iUPD with pathogenic variants causing recessive disease.

SUBMITTER: Qian Y

PROVIDER: S-EPMC8134681 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

Dataset Information

Case Report: Complete Maternal Uniparental Isodisomy of Chromosome 5 (iUPD(5)mat) With PCSK1 Nonsense Variant in an Infant With Recurrent Diarrhea.

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