Abstract：
Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.
Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).
Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.
We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).
Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.
We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
摘要：
目的：在Fryns综合征中已经描述了双等位基因PIGN变异，多发性先天性异常-张力减退-癫痫综合征（MCAHS），和神经表型。尚未报道与基因型有关的全部临床表现。
方法：对61例双等位基因PIGN病例的基因型和表型数据进行整理和分析：21例新病例和40例以前发表的病例。对2个复发变体(c.2679C>Gp.Ser893Arg和c.932T>Gp.Leu311Trp)进行功能分析。
结果：在16例Fryns综合征患者中检测到双等位基因截短变异，1具有MCAHS1，2具有Fryns综合征/MCAHS1，3具有神经表型。在该组中，产前或新生儿死亡的风险增加（6例死亡发生在子宫内或出生后2个月内；6例妊娠终止）。羊水过多的发生率，先天性异常（例如，膈疝)，畸形显著增加。其余45例报告了双等位基因错义或混合基因型-32例显示神经系统表型，12例具有MCAHS1。该组中没有看到膈疝或腹壁缺损的病例，除了患者1，我们发现错义变异p.Ser893Arg导致功能无效等位基因，这表明在最后的外显子中可能存在未描述的功能重要区域。对于所有基因型，在新生儿期存活的患者中，发育延迟的外显率和癫痫发作和张力减退的外显率接近完全。
结论：我们扩展了与双等位基因PIGN变异相关的表型和自然史的描述谱。我们的研究表明，双等位基因截断变异通常会导致更严重的弗林综合征表型，但是神经问题，比如发育迟缓，癫痫发作,和低张力,存在于所有基因型中。当基因型与预测的表型不相关时，应考虑功能分析，因为PIGN中可能存在尚未发现的其他功能重要区域。
方法：对61例双等位基因PIGN病例的基因型和表型数据进行整理和分析：21例新病例和40例以前发表的病例。对2个复发变体(c.2679C>Gp.Ser893Arg和c.932T>Gp.Leu311Trp)进行功能分析。
结果：在16例Fryns综合征患者中检测到双等位基因截短变异，1具有MCAHS1，2具有Fryns综合征/MCAHS1，3具有神经表型。在该组中，产前或新生儿死亡的风险增加（6例死亡发生在子宫内或出生后2个月内；6例妊娠终止）。羊水过多的发生率，先天性异常（例如，膈疝)，畸形显著增加。其余45例报告了双等位基因错义或混合基因型-32例显示神经系统表型，12例具有MCAHS1。该组中没有看到膈疝或腹壁缺损的病例，除了患者1，我们发现错义变异p.Ser893Arg导致功能无效等位基因，这表明在最后的外显子中可能存在未描述的功能重要区域。对于所有基因型，在新生儿期存活的患者中，发育延迟的外显率和癫痫发作和张力减退的外显率接近完全。
结论：我们扩展了与双等位基因PIGN变异相关的表型和自然史的描述谱。我们的研究表明，双等位基因截断变异通常会导致更严重的弗林综合征表型，但是神经问题，比如发育迟缓，癫痫发作,和低张力,存在于所有基因型中。当基因型与预测的表型不相关时，应考虑功能分析，因为PIGN中可能存在尚未发现的其他功能重要区域。
