Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain.
Front Endocrinol (Lausanne). 2023 Jan 4;13:1055431. doi: 10.3389/fendo.2022.1055431. eCollection 2022.
iPPSD2 (which includes PHP1A and PPHP/POH) is a rare inherited autosomal dominant endocrine disorder caused by inactivating pathogenic variants. A high percentage of cases has been suggested. In rare cases, parental mosaicism has been described, but its real frequency is unknown.
A retrospective study including a series of 95 genetically confirmed iPPSD2 probands.
The frequency of cases was evaluated and the distribution of the type of variants was compared according to the type of inheritance. The putative involved allele was determined by reverse transcriptase PCR (RT-PCR) or allele specific oligonucleotide RT-PCR (ASO-RT-PCR). The possibility of mosaicism was studied by next-generation sequencing (NGS) on the corresponding parental DNA.
In 41 patients the variant was of origin and in 24 the origin could not be established. In both cases 66.67% of variants generated a truncated or absent protein whereas the rest of the variants were missense or in-frame deletion/duplication. Parental origin was studied in 45 of those patients and determined in 35. Curiously, the percentage of variants at the paternal allele was higher than when paternally inherited (31.1% vs 6.67%). NGS detected mosaicism in three independent families: one from paternal DNA (allelic ratio 10%) and two from maternal DNA (allelic ratio 10% and 2%).
pathogenic variants are frequent in iPPSD2 (around 45%). Parental mosaicism is infrequent (8.11%) but should be analyzed with NGS, taking into account its importance in genetic counselling.
iPPSD2（包括 PHP1A 和 PPHP/POH）是一种罕见的遗传性常染色体显性内分泌疾病，由致病性变异体失活引起。有研究表明，这种疾病的发病率较高。在极少数情况下，已经描述了父母镶嵌现象，但其实验室频率尚不清楚。
一项回顾性研究，纳入了 95 例经基因证实的 iPPSD2 先证者。
评估病例的频率，并根据遗传方式比较变异类型的分布。通过逆转录 PCR（RT-PCR）或等位基因特异性寡核苷酸 RT-PCR（ASO-RT-PCR）确定潜在涉及的等位基因。通过下一代测序（NGS）对相应的父母 DNA 研究嵌合体的可能性。
在 41 例患者中，变异源于父本，在 24 例患者中无法确定其来源。在这两种情况下，66.67%的变异产生截短或缺失的蛋白质，而其余变异为错义或框内缺失/重复。对其中 45 例患者的父母来源进行了研究，并在 35 例中得到了确定。有趣的是，父本等位基因的致病性变异百分比高于父系遗传时（31.1%比 6.67%）。NGS 在三个独立的家庭中检测到嵌合体：一个来自父本 DNA（等位基因比例为 10%），两个来自母本 DNA（等位基因比例为 10%和 2%）。
iPPSD2 中致病性变异较为常见（约 45%）。父母镶嵌现象罕见（8.11%），但应进行 NGS 分析，考虑到其在遗传咨询中的重要性。
