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.
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