Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2^nd or 3^rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.

主要抗体缺陷（PAD）是原发性免疫缺陷最常见的形式，其特点是广泛的临床、免疫学和遗传异质性。利用当前全外显子组测序的黄金标准进行诊断，仅在不到 20% 的患者中发现致病基因变异。虽然对 PAD 致病基因的阐明为了解疾病发病机制的细胞和分子机制提供了许多见解，但许多其他基因可能尚未定义，无法对患者进行明确的诊断、预后监测和靶向治疗。^{考虑到许多患者在生命的第二个}或第三^个十年中表现出相对较晚的疾病表现，因此单一遗传病变是否是所有患者疾病的基础是值得怀疑的。其他基因变异和/或非遗传因素（包括特定感染）的综合影响可能会导致疾病的出现。在这篇综述中，我们定义了 (1) PAD 的临床和免疫学变异性，(2) 考虑 PAD 中发现的遗传缺陷如何深入了解 B 细胞免疫生物学，(3) 解决基因组学的最新技术进展以及与识别因果变异，(4) 讨论如何对未知意义的变异进行功能验证，从而提高 PAD 患者的诊断率、改善预后监测和个性化医疗。多学科方法将是减少这种免疫疾病的早期死亡率和高发病率的关键。