Correcting Lab Misinterpretations of Variants of Unknown Significance: A Case Study of EMILIN1 Variants in an Autosomal Recessive Disorder

A nine-month-old male was referred with short stature, tortuosity in multiple arteries, pulmonary stenosis, and multiple fractures. Trio exome sequencing (ES) revealed a c.275_277delinsTT, p.(C92Ffs<i>22)</i> maternal variant <i>and a</i> c.1759G>T, p.(G587) paternal EMILIN1 variant. The lab report classified his biallelic EMILIN1 terminator variants as variants of unknown significance (VUSs) and did not postulate a possible relationship with a known autosomal recessive disorder. While EMILIN1 is listed in OMIM as causing an autosomal dominant disorder (OMIM # 620080), there are no current OMIM entries for clinically heterogeneous disorders with an autosomal recessive mode of inheritance variants. Importantly, at that time, biallelic loss-of-function variants in EMILIN1 had already been shown to cause an autosomal recessive disorder characterized by cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility. However, the close overlap of his pleiotropic features was not acknowledged. We informed his parents that he very likely had this known condition, despite the benign lab interpretation. This scenario illustrates the potential need for clinicians and genetic counselors to carefully review and, in some cases, correct misinformed lab reports.