Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

Monogenic Inflammatory Bowel Disease: It's Never Too Late to Make a Diagnosis.

Background: More than 50 different monogenic disorders have been identified as directly causing inflammatory bowel diseases, typically manifesting in the first years of life. We present the clinical course and immunological work-up of an adult patient who presented in adolescent years with an atypical gastrointestinal phenotype and was diagnosed more than two decades later with a monogenic disorder with important therapeutic implications. Methods: Whole exome sequencing was performed in a 37-years-old patient with a history of diarrhea since adolescence. Sanger sequencing was used to validate the suspected variant. Mass cytometry (CyTOF) and flow cytometry were conducted on peripheral blood mononuclear cells for deep immunophenotyping. Next-generation sequencing of the TCRB and IgH was performed for global immune repertoire analysis of circulating lymphocytes. Results: We identified a novel deleterious c.1455C>A (p.Y485X) mutation in LRBA. CyTOF studies demonstrated significant changes in immune landscape in the LRBA-deficient patient, including an increase in myeloid derived suppressor cells and double-negative T cells, decreased B cells, low ratio of naïve:memory T cells, and reduced capacity of T cells to secrete various cytokines following stimulation, including tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). In addition, this patient exhibited low frequency of regulatory T cells, with a reduction in their CTLA4 expression and interleukin (IL)-10 secretion. Finally, we show marked oligoclonal expansion of specific B- and T-cell clones in the peripheral blood of the LRBA-deficient patient. Conclusions: LRBA deficiency is characterized by marked immunological changes in innate and adaptive immune cells. This case highlights the importance of advanced genetic studies in patients with a unique phenotype, regardless of their age at presentation.