19. De novo homozygous variant due to uniparental isodisomy results in a recessive disorder

A 10-month old male presented with developmental delay, hypotonia, microcephaly, and sparse, coarse hair. He was born at 38 weeks’ gestation to a 33-year-old G1P0 mother. Brain MRI revealed delayed myelination but otherwise normal appearance of the brain. In addition, he has had significant delay in reaching developmental milestones but has been making improvements with physical and speech therapy. In order to look for an underlying genetic cause for his clinical features, we performed whole-genome SNP microarray analysis. No significant copy number changes were detected. However, we did observe absence of heterozygosity for the entire chromosome 7, consistent with uniparental isodisomy (UPiD). UPiD occurs when identical chromosomes are inherited from the same parent putting offspring at risk for imprinting disorders, mosaic aneuploidy and recessive disorders. Since our patient's clinical features were not consistent with Russell-Silver syndrome caused by matUPD7, we preformed trio whole exome sequencing (WES) to look for variation on chromosome 7 that could unmask a recessive condition. WES analysis identified only homozygous variants on chromosome 7 supporting patUPiD7. Additionally, we identified a pathogenic homozygous c.135C>A (p.Try45*) variant in the MPLKIP gene. Biallelic variants in MPLKIP cause autosomal recessive trichothiodystrophy 4, a disorder characterized by sulfur-deficient brittle, sparse hair, mental and physical delay, and microcephaly, similar to the clinical features found in our patient. Surprisingly, parental studies indicated that this alteration was de novo in our patient. We propose this occurred from a maternal meiosis nondisjunction event that produced a nullisomic gamete. The monosomic conception formed was then postzygotically rescued prior to the formation of the embryo, explaining the patUPiD found in our patient. Generally, heterozygous de novo variants in genes associated with autosomal recessive conditions are not causative; however, in the context of UPiD and monosomy rescue a sporadic variant can be homozygous and therefore disease causing.