The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1-related disorders.

中文翻译：

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与 POP1 基因纯合可能致病变异相关的新表型

POP1 基因的双等位基因变异与发育不良 (AAD OMIM 607095) 相关，这是一种罕见的骨骼发育不良，其特征是产前四肢根茎缩短和全身关节过度活动。受影响的个体通常具有正常的神经发育里程碑。在这里，我们介绍了来自同一家庭的三个病例，这些病例可能具有致病性纯合POP1变异和全新的表型：一名患有整体发育迟缓和自闭症、小头畸形、特殊畸形特征和多种先天性异常的女孩。随后的两次妊娠均因多种先天畸形而终止。胎儿 DNA 样本显示 POP1 基因存在相同的纯合变异。与对照相比，先证者中 RMRP 的表达降低，并且在该变异携带者的杂合父母中略有降低。据我们所知，这是这种新表型的首次报告，该表型与POP1 中一种新的可能致病变异相关。我们的研究结果扩大了 POP1 相关疾病的表型谱。