LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy

Abstract

LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.

Keywords: LRBA deficiency; comparative genomic hybridization array; primary immunodeficiency; uniparental disomy; whole exome sequencing.

Figure 1

Segmental isodisomy of maternal origin containing the c.3366insA LRBA mutation. The LOH region in chromosome 4 of the patient is indicated by a red line. The LOH region, detected by analyzing WES data, includes four genes (LRBA, RPS3A, SH3D19, and PRSS48). A diagram of the LRBA gene with its 58 exons is shown. The 10 CGH array probes located along the LRBA gene are depicted with green symbols. All LRBA probes displayed a normal signal, confirming a copy number-neutral region. The c.3366insA mutation is shown in red (electropherograms of the patient and her parents). Five common SNPs surrounding the LRBA mutation are also shown in blue. The genotype of the patient (P) and her mother (M) and father (F) are indicated using the numbers 0 and 1 for the 2 possible alleles. Array-CGH data spanning the LOH and flanking regions is shown. gDNA from patient and father was labeled with Cy3 (red) and control gDNA with Cy5 (blue). The pedigree of the family shows the inherited chromosome 4, with the segmental isodisomy of maternal origin.