Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding Gs α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The mother-specific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of Gs α in oocyte biology or embryogenesis, with implications for genetic counseling. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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GNAS 功能丧失突变的母体传输率失真。

假性甲状旁腺功能减退症 1A 型 (PHP1A) 和假性假性甲状旁腺功能减退症 (PPHP) 是两种罕见的常染色体显性遗传疾病，由编码 Gs α 的印迹鸟嘌呤核苷酸结合蛋白 α 刺激活性 (GNAS) 基因的功能丧失突变引起。PHP1A 是由母体等位基因突变引起的，导致奥尔布赖特遗传性骨营养不良 (AHO) 和激素抵抗，主要是对甲状旁腺素 (PTH)，而具有 AHO 特征且没有激素抵抗的 PPHP 与父系等位基因突变有关。本研究旨在调查 GNAS 突变的亲代传播。我们对 204 个家庭和 361 名携带 GNAS 突变的患者进行了一项回顾性研究。为防止由于收集数据的方式而导致确定偏向于更高比例的受影响儿童，我们从传输分析中排除了已确定同胞中的所有先证者。偏差校正后，根据观察到的核心家族后代的基因型计算突变等位基因的分布比例，并与根据孟德尔遗传（单样本Z检验）的预期比例50%进行比较。还分析了性别比、传递亲本的表型和取决于突变严重程度的传递。在 114 个核心家庭中进行了传播分析，包括 250 个后代。男性和女性患者的生育率相似。我们发现突变等位基因从母亲到后代的传播过多（59%，p = .022），当突变严重时，这种传播更大（61.7%，p = .023）。相似地，当母亲具有 PHP1A 表型时发现过度传播 (64.7%, p = .036)。相比之下，当突变是父系遗传时，观察到孟德尔分布。还观察到携带者中有更多的女性，但在非携带者中没有。与 PHP1A 相关的母亲特异性传输比率失真 (TRD) 和性别比率不平衡表明 Gs α 在卵母细胞生物学或胚胎发生中的作用，对遗传咨询有影响。© 2019 美国骨与矿物研究学会。与 PHP1A 相关的母亲特异性传输比率失真 (TRD) 和性别比率不平衡表明 Gs α 在卵母细胞生物学或胚胎发生中的作用，对遗传咨询有影响。© 2019 美国骨与矿物研究学会。与 PHP1A 相关的母亲特异性传输比率失真 (TRD) 和性别比率不平衡表明 Gs α 在卵母细胞生物学或胚胎发生中的作用，对遗传咨询有影响。© 2019 美国骨与矿物研究学会。