Abstract
Epidermolysis bullosa (EB) is a genetically heterogeneous skin fragility disorder. Some subtypes also involve other organs, including the pulmonary, gastrointestinal, and renal systems. One severe form, junctional epidermolysis bullosa (JEB), is characterized by cleavage within the skin layers. The rarest and most lethal spectrum of this disorder includes pyloric atresia (PA), known as JEB-PA. The number of reported cases in Thailand is limited. Using trio whole exome sequencing, we identified a Thai newborn with lethal JEB-PA caused by novel null compound heterozygous variants in ITGB4. The patient carries a known nonsense variant (c.2533C>T) and a novel frameshift indel variant (c.1614delT) in ITGB4, inherited from her parents. Both are null variants that result in a premature termination codon (PTC). A comprehensive review of existing literature was conducted to gather information on disease-causing variants and genotype-phenotype correlations in JEB-PA. We summarized 50 previously reported JEB-PA cases, detailing disease severity and ITGB4 variants. We found that nonsense and frameshift indels were predominant in lethal cases (32/62 alleles), whereas missense variants were more common in nonlethal forms (18/38 alleles). Pathogenic variants were most frequently located in the Fibronectin II-like domain (FnIII) and cytoplasmic domain (CP) for null variants and in the von Willebrand factor Type A (VWFA) domain for missense variants. We emphasize the importance of genetic testing in these heterogeneous skin disorders. Molecular results reveal the disorder's diagnosis, provide a precise prognosis, and guide the genetic counseling process for the family. Moreover, understanding pathomolecular mechanisms can lead to potential future treatments.