Classification of Uniparental Isodisomy Patterns That Cause Autosomal Recessive Disorders: Proposed Mechanisms of Different Proportions and Parental Origin in Each Pattern

Abstract

Patients with autosomal recessive (AR) disorders are usually born to parents both of whom are heterozygous carriers of the disease. However, in some instances only one of the parents is a carrier and a mutation is segregated to the patient through uniparental isodisomy (UPiD). Recently, an increasing number of such case reports has been published, and it has become clear that there are several different UPiD patterns that cause AR disorders. In this article, we report 3 remarkable patients with different patterns of UPiD. We then review 85 cases collected in the literature. We realized that they can be classified into 3 patterns: UPiD of the whole chromosome, segmental UPiD with uniparental heterodisomy (UPhD), and segmental UPiD caused by post-zygotic mitotic recombination (MiRe). Whole chromosomal UPiD accounted for the majority of cases, with paternal origin accounting for approximately twice as many cases as maternal origin. Most cases of segmental UPiD with UPhD were of maternal origin, with a dominancy of nondisjunction in meiosis I, while segmental UPiD through MiRe is the smallest pattern with equal parental origin. These differences in proportion and parental origin in each pattern can be explained by considering nondisjunction during oogenesis as the starting point and UPiD as subsequent events.

De novo unbalanced translocations have a complex history/aetiology

“…Furthermore, in unbalanced translocations originating from partial trisomy rescue, if the chromotripsis would occur on the supernumerary chromosome of paternal origin, the following maternal hetero/isodisomy for the remaining two chromosomes might generate further pathogenicity (Niida et al 2018) either by reducing to homozygous state diseasecausing variants present in the mother at heterozygous state, or due to the presence of imprinted genes that are expressed by the paternal allele only.…”

A case of early‐onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy

“…UPD is a rare genetic condition in which both chromosomal homologs originate from one parent (Engel, ). UPD can be classified by structural changes; the affected region extends to the whole chromosome (complete) or part of the chromosome (segmental), and allelic status: having two identical copies of the same chromosome (isodisomy, UPiD) or two distinct copies of the chromosomes inherited from one parent (heterodisomy, UPhD) (King et al, ; Niida, Ozaki, Shimizu, Ueno, & Tanaka, ). UPiD can cause autosomal recessive disorders if the chromosome possessing a disease‐causing variant is transmitted to the patient.…”

“…Here, both UPiD and UPhD regions were observed in chromosome 16. The UPhD of chromosome 16 with segmental UPiD could be explained by the recombination at the 16p13.3‐p13.13 region and the nondisjunction of chromosome 16 in meiosis I, following the elimination of paternal chromosome 16 by trisomy rescue (Niida et al, ).…”

Warburg Micro Syndrome 1 due to Segmental Paternal Uniparental Isodisomy of Chromosome 2 Detected by Whole-Exome Sequencing and Homozygosity Mapping

“…Imprinting disorders have not been described for UPDs of some chromosomes including chromosome 2, regardless of paternal or maternal, while UPDs of chromosomes 6, 7, 11, 14, 15, and 20 are related to imprinting disorders due to their parent-oforigin [Bastepe et al, 2001;Liehr, 2010;Mulchandani et al, 2016]. An increasing number of uniparental isodisomy (UPiD) cases have been reported in autosomal recessive diseases because of the more frequent use of new generation techniques such as single-nucleotide polymorphism array and next-generation sequencing [Niida et al, 2018]. Here, we report on a patient with a homozygous pathogenic variant in the RAB3GAP1 gene due to segmental UPiD of chromosome 2 found by homozygosity mapping analysis of whole-exome sequencing (WES) data in addition to segregation analyses.…”