Concomitant Ultrarare Mutations in TLR3 and CTPS2 in a Patient with Severe and Recurrent Respiratory Infections in Early Life

To the Editor,

Here we report the case of an Arab boy with parents of fourth-degree consanguinity (Fig. 1a), with a history of multiple hospitalizations in early life due to recurrent viral lower respiratory tract infections. The boy is the only affected family member. Whole genome sequencing of the boy and family members revealed a biallelic, hypomorphic missense mutation in the TLR3 gene (c.2228G > A, p.Gly743Asp) in the patient (Figure S1), which is ultrarare and predicted to be pathogenic (Table S1). The allele has previously been reported in a single case with herpes simplex encephalitis due to a carrier of two cis variants in TLR3 gene [1]. We also found one of the older, unaffected female siblings to carry the same biallelic TLR3 missense mutation, suggesting incomplete penetrance. Both parents and two other female siblings are heterozygous carriers (Fig. 1a). In addition, we found an ultrarare hemizygous variant in CTPS2 (c.1585T > G, p.Phe529Val) in the patient (Figure S1), which is private to the family. While this CTPS2 variant is predicted to be probably pathogenic (Table S1) and further in silico analysis suggests that the variant may cause local destabilization of the protein structure (Figure S2), comparative immunoblot analyses of activated T cells from the patient, relatives and unrelated healthy donors shows that the CTPS2 protein expression is not altered in the patient (Figure S3). Additional genotyping also including one extended family member revealed that the father, a maternal uncle and two female siblings are hemizygous and homozygous for the wild-type CTPS2 allele, respectively, while the mother and one female sibling are heterozygous carriers of the CTPS2 missense variant (Fig. 1a). Unfortunately, we were unable to genotype additional extended family members to identify another male family member potentially carrying the CTPS2 missense allele. Thus, the significance of this latter variant in CTPS2 remains uncertain. Both variants in TLR3 and CTPS2 were confirmed by Sanger sequencing (Fig. 1b and 1c).