133. Incidental finding of the 1st degree of parental relatedness in a newborn with JBS and homozygous UBR1 mutation

Abstract

A 2-month-old newborn girl presented multiple congenital anomalies at birth, including ventriculomegaly, imperforate anus, absent nasal alae, absent corpus callosum, anemia, need for thermoregulation, feeding difficulty and failure to thrive. Clinical features are suggestive of autosomal recessive Johanson-Blizzard syndrome (JBS). Rapid interphase FISH of peripheral blood using centromere probes for X, Y and 18 was normal, and G-banding at 550 band levels showed a normal female karyotype. Whole genome microarray analysis using Affymetrix CytoScan® Dx showed no clinically significant copy number changes. However, the SNP analysis identified 30 regions of homozygosity (ROH)>5 Mb involving 17 autosomes and totaling ∼600 Mb (∼21.6% of ∼2,782 Mb total autosome length); which suggests a 1st degree of parental relatedness (ave. 25%; 95% CI: 21.3-28.7%; PMID: 22858719, 25118026). Such ROHs increase risk for imprinting and/or recessive Mendelian disorders. Noticeably, there was a 74 Mb ROH region in 15q11.2q26.2 encompassing UBR1 gene at 15q15.2, which pointed to possible homozygosity of an UBR1 mutation causing JBS. As expected, Next Generation Sequencing identified a homozygous UBR1 variant at C.1993C>T, exon 17 (UBR1, NM_174916.2), which is predicted to cause a premature protein termination p.(Arg665*). This variant is interpreted pathogenic, as it was reported in a patient with JBS (PMID:24599544) and multiple protein truncating variants were reported to be pathogenic in this gene. These findings supported a diagnosis of JBS in this proband. Our case illustrates that identification of ROHs can aid in investigation and diagnosis of autosomal diseases.