Individuals with JAK1 variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis.

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, treatment of one affected patient with severe atopic dermatitis using the JAK1/JAK2-selective inhibitor, baricitinib, resulted in clinically significant improvement. These findings suggest that individually rare JAK1 GoF variants may underlie an emerging syndrome with more common presentations of autoimmune and inflammatory disease (JAACD syndrome). More broadly, individuals who present with such conditions may benefit from genetic testing for the presence of JAK1 GoF variants.

TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

BACKGROUND: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance. OBJECTIVE: We sought to define TCF3 haploinsufficiency (HI) biology and its association with immunodeficiency. METHODS: Patient clinical data and blood samples were analyzed. Flow cytometry, Western blot analysis, plasmablast differentiation, immunoglobulin secretion, and transcriptional activity studies were conducted on individuals carrying TCF3 variants. Mice with a heterozygous Tcf3 deletion were analyzed for lymphocyte development and phenotyping. RESULTS: Individuals carrying monoallelic LOF TCF3 variants showed B-cell defects (eg, reduced total, class-switched memory, and/or plasmablasts) and reduced serum immunoglobulin levels; most but not all presented with recurrent but nonsevere infections. These TCF3 LOF variants were either not transcribed or translated, resulting in reduced wild-type TCF3 protein expression, strongly suggesting HI pathophysiology for the disease. Targeted RNA sequencing analysis of T-cell blasts from TCF3-null, dominant negative, or HI individuals clustered away from healthy donors, implying that 2 WT copies of TCF3 are needed to sustain a tightly regulated TCF3 gene-dosage effect. Murine TCF3 HI resulted in a reduction of circulating B cells but overall normal humoral immune responses. CONCLUSION: Monoallelic LOF TCF3 mutations cause a gene-dosage-dependent reduction in wild-type protein expression, B-cell defects, and a dysregulated transcriptome, resulting in immunodeficiency. Tcf3+/- mice partially recapitulate the human phenotype, underscoring the differences between TCF3 in humans and mice.

Kleefstra syndrome: Impact on parents.

BACKGROUND: Kleefstra syndrome (KS) is associated with developmental delay, autism, intellectual disability, psychosis, and regression. Research has not been conducted to assess the impact of KS on parents. OBJECTIVE/HYPOTHESIS: A mixed-method study was conducted to assess the impact on parental well-being by evaluating parents' well-being, identifying factors of parental experience predicting well-being, and exploring the parental experience. METHODS: Parents completed an online survey containing the PedsQL™ Family Impact Module (FIM) and a questionnaire created by the researchers. One-Way T-Test compared parents of children with KS to parents of children with Prader-Willi syndrome (PWS). Multiple linear regression used parents' total scale scores on PedsQL™ FIM to identify factors influencing parental well-being. Constant comparative analysis used open-ended responses to explore the parental experience of having a child with KS. RESULTS: Parents of children with KS had statistically lower scores in daily activity and social functioning, but statistically higher scores in communication and emotional functioning compared to parents of children with PWS. However, the power was below 0.80, meaning additional research needs to be completed to confirm these findings. The linear multiple regression was not significant. Most importantly, the themes of establishing the diagnosis, importance of knowledge, sense of community, KS and relationships with others, how life changed, and what the future will hold, characterized the parental experience. CONCLUSIONS: Knowledge and support were important to parents who had a child recently diagnosed with KS. Therefore, parents should be provided resources about KS and support groups at diagnosis.

WNT10A Mutation Causes Ectodermal Dysplasia in a Patient Mosaic for Turner Syndrome.

WNT10A plays a role in the proper proliferation and differentiation of ectodermal structures. Mutations in this gene can be responsible for a highly phenotypically variable range of disorders termed ectodermal dysplasias. Here, we describe the case of a five-year-old male patient who is mosaic for Turner syndrome (45,X [90%]/46,X isodicentric Y [10%]) and who presented to dermatology with anhidrosis, conical-shaped teeth, and a slowed rate of hair growth with genetic testing subsequently revealing a likely pathogenic heterozygous variant in WNT10A (c.682T>A; p.Phe228Ile). Future investigation into the WNT10A pathway, which is regulated downstream by ß-catenin, might allow topical therapeutics to be developed that promote normal ectodermal growth and differentiation. Current management for this patient includes precautions taken to prevent overheating and heat stroke and close dermatological and dental monitoring.