AUTHOR=Moch Johanna , Radtke Maximilian , Gburek-Augustat Janina , Karnstedt Maike , Schönnagel Senta , Drukewitz Stephan H. , Pilgram Laura , Hentschel Julia , Schumann Isabell 

TITLE=Case report: Complete paternal isodisomy on chromosome 18 induces methylation changes in PARD6G-AS1 promotor in a case with arthrogryposis

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1297754

DOI=10.3389/fgene.2023.1297754

ISSN=1664-8021

ABSTRACT=<p>Uniparental disomy (UPD) is the inheritance of both alleles of a chromosome from only one parent. So far, the detection of UPDs in sequencing data is not well established and a known gap in next-generation sequencing (NGS) diagnostics. By developing a new tool for UPD detection, we re-evaluated an eight-year-old individual presenting with scoliosis, muscle weakness and global developmental delay. Previous panel analysis identified a homozygous likely pathogenic loss-of-function variant in the <italic>PIEZO2</italic>-gene associated with arthrogryposis (OMIM # 617146). Interestingly, during a re-evaluation process, we identified a region of homozygosity (ROH) covering over 95% of chromosome 18. Segregation and microsatellite analysis within the family revealed that only the father is a heterozygous carrier of the variant in <italic>PIEZO2</italic> and confirmed paternal uniparental isodisomy (iUPD) on chromosome 18 in the individual. Further methylation analysis indicated demethylation of the promotor region of <italic>PARD6G-AS1</italic>, which is described to be maternally imprinted and could possibly influence the individuals’ phenotype. Our report describes the first complete iUPD on chromosome 18 and highlights that UPDs can be a cause for homozygous pathogenic variants, which reduces the risk of reoccurrence in case of a new pregnancy in comparison to an autosomal recessive inheritance trait significantly.</p>