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.
Highlights
Congenital diarrhea diseases (CDDs) are a heterogeneous group of conditions characterized by watery diarrhea and are the major cause of neonatal mortalities worldwide (Younis et al, 2020)
Four genes are reported to be related to enteroendocrine cell dysfunction, including NEUROGS, PCSK1 (Younis et al, 2020), and genes causing a syndromic disease with diarrhea—ARX and RFX
Trio-exome sequencing (Trio-ES) data showed that 97.9% (1168/1193) variants had a B Allele Frequency” (BAF) higher than 0.95 on chromosome 5, meaning the absence of heterozygosity (AOH), which is inherited from the mother (Figure 2A)
Summary
Congenital diarrhea diseases (CDDs) are a heterogeneous group of conditions characterized by watery diarrhea and are the major cause of neonatal mortalities worldwide (Younis et al, 2020). Trio-ES data showed that 97.9% (1168/1193) variants had a BAF higher than 0.95 on chromosome 5, meaning the absence of heterozygosity (AOH), which is inherited from the mother (Figure 2A). A homozygous nonsense variant in PCSK1 (NM_000439: c.238C>T, p.Arg80Ter) was detected in the proband, while her mother was a heterozygous carrier and her father was normal (Figure 2C). This variant was confirmed by Sanger sequencing (Figure 2D). Combining the clinical phenotype (continuous neonatal diarrhea, BMI increase) and the molecular genetic finding, the proband was diagnosed with congenital proprotein convertase 1/3 deficiency caused by a PCSK1 homozygous pathogenic variant due to iUPD(5)mat
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