Iterative genetic testing identifies SAMHD1 deficiency caused by a homozygous balanced translocation

We present a patient with complex symptoms, including those consistent with familial chilblain lupus (FCL). A de novo likely pathogenic variant in MN1 explains observed microcephaly, sensorineural hearing loss, growth restriction, and mild dysmorphism, but not perniosis with acral autoamputation, small joint arthritis, and immune abnormalities. Transcriptomics revealed a type I IFN signature and strong downregulation of SAMHD1, which is associated with a spectrum of interferonopathies, including FCL. RNA reads from only the first 4 exons of SAMHD1 were detectable, with no coverage of exon 5 onward. Subsequent long-read genome sequencing identified a homozygous, balanced, reciprocal translocation from the SAMHD1 locus on chromosome 20 (q11.23) to chromosome 17 (p11.2). Utilizing an iterative genetic testing approach encompassing exomic, transcriptional, and genomic readouts was invaluable for elucidating the uncommon structural variation carried by this patient. Autozygous balanced, reciprocal translocations are extremely rare, and this appears to be the first case of any inborn error of immunity attributed to this mode of inheritance.