Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia

Abstract

Introduction: Genetic aberrations associated with combined immunodeficiency have been increasingly identified in the past two decades. Yet, there are still 30% of these patients with unidentified genetic cause. Methods: We employed whole genome sequencing to identify the genetic defect leading to combined immunodeficiency. Thymus, gut, and lung tissues were studied using hematoxylin and eosin staining as well as immunohistochemistry. Results: We identified 2 deleterious mutations in the TTC7A gene. Surprisingly, the patient did not have intestinal atresia but suffered repeated infections as well fatal pneumonitis. Dendriform lung ossification developed, which was unique to this case. The patient had typical presentation of combined immunodeficiency including profound lymphopenia, markedly reduced in-vitro response to mitogens, as well as low TRECS. Serum immunoglobulins were also markedly reduced. Conclusion: Mutations in the TTC7A gene can cause combined immunodeficiency with no intestinal atresia and predispose to lung ossification. Statement of novelty: TTC7A mutations can cause profound immunodeficiency without multiple intestinal atresia. We report here for the first time that this defect is associated with dendriform lung ossification.