Pituitary stalk interruption syndrome (PSIS) is a type of congenital malformation of the anterior pituitary, which leads to isolated growth hormone deficiency or multiple hypothalamic‐pituitary deficiencies. Many genetic factors have been explored, but they only account for a minority of the genetic aetiology. To identify novel PSIS pathogenic genes, we conducted whole‐exome sequencing with 59 sporadic PSIS patients, followed by filtering gene panels involved in pituitary development, holoprosencephaly and midline abnormality. A total of 81 heterozygous variants, distributed among 59 genes, were identified in 50 patients, with 31 patients carrying polygenic variants. Fourteen of the 59 pathogenic genes clustered to the Hedgehog pathway. Of them, PTCH1 and PTCH2, inhibitors of Hedgehog signalling, showed the most frequent heterozygous mutations (22%, seven missense and one frameshift mutations were identified in 13 patients). Moreover, five novel heterozygous null variants in genes including PTCH2 (p.S391fs, combined with p.L104P), Hedgehog acyltransferase (p.R280X, de novo), MAPK3 (p.H50fs), EGR4 (p.G22fs, combined with LHX4 p.S263N) and SPG11 (p.Q1624X), which lead to truncated proteins, were identified. In conclusion, genetic mutations in the Hedgehog signalling pathway might underlie the complex polygenic background of PSIS, and the findings of our study could extend the understanding of PSIS pathogenic genes.

中文翻译：

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通过全外显子测序鉴定垂体柄中断综合征中新的候选致病基因。

垂体秆中断综合征（PSIS）是垂体前叶的一种先天性畸形，导致孤立的生长激素缺乏症或下丘脑-垂体多发性缺陷。已经探索了许多遗传因素，但它们仅占遗传病因学的一小部分。为了鉴定新的PSIS致病基因，我们对59名散发性PSIS患者进行了全外显子测序，然后过滤了涉及垂体发育，全前脑畸形和中线异常的基因组。在50例患者中鉴定出81个杂合变异体，分布在59个基因中，其中31例携带多基因变异体。59个致病基因中有14个聚集在Hedgehog途径上。其中的PTCH1和PTCH2是刺猬信号的抑制剂，显示出最常见的杂合突变（在13例患者中鉴定出22％，7个错义和1个移码突变）。此外，基因中的五个新的杂合无效变体包括PTCH2（p.S391fs，与p.L104P结合），刺猬酰基转移酶（p.R280X，从头），MAPK3（p.H50fs），EGR4（p.G22fs，与LHX4 p.S263N结合）和SPG11（p.Q1624X ），导致截断的蛋白质，已被鉴定。总之，Hedgehog信号通路中的基因突变可能是PSIS复杂的多基因背景的基础，我们的研究结果可以扩展对PSIS致病基因的了解。