Identification of a Founder GLDN Variant Associated With "Lethal" Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long-Term Survivors' Management.

IF 1.7 4区 生物学 Q3 GENETICS & HEREDITY
Alexa McAdam, Yoko A Ito, Marilyn Richard, Dan Spiegelman, Daniel Rochefort, Lan Xiong, Maryam Oskoui, David Zielinski, Guy A Rouleau, Sirui Zhou, Kym M Boykott, Isabelle De Bie
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Abstract

Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.82G >C p.(Ala28Pro)] in GLDN. Two pregnancies presented with significant obstetrical complications including placental abruption and hemorrhage. Four infants died shortly after birth, while one survived past the neonatal period. This individual, while apparently asymptomatic during infancy, then presented with progressive neuromuscular and respiratory compromise that became more evident in adolescence. Data from a Nunavik Inuit cohort demonstrated a minor allele frequency (MAF) of 0.03571 for this variant compared to 0.00001341 in the general population, suggesting a founder effect in the Nunavik Inuit population. Our findings support the presence of a founder variant associated with LCCS11 in Nunavik Inuit populations. Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal, but long-term survivors are at risk of progressive neuromuscular compromise. We also highlight in this report the significant obstetrical complications associated with this fetal-onset condition.

努纳维克因纽特人与“致死性”关节挛缩相关的GLDN变异的鉴定:对产科和长期幸存者管理的影响。
GLDN的双等位基因变异最近与致死性先天性挛缩综合征(LCCS11)有关,LCCS11是一种具有高新生儿死亡率的胎儿运动缺陷变形序列(FADS)。在本报告中,我们描述了来自努纳维克不同社区的两个加拿大因纽特人家庭的五个人,他们都患有FADS,并携带一种罕见的纯合错义变体[NM_181789.4:c]。82G >C p.(Ala28Pro)]在GLDN。2例妊娠表现出显著的产科并发症,包括胎盘早剥和出血。4名婴儿在出生后不久死亡,1名活过了新生儿期。该患者在婴儿期无明显症状,随后出现进行性神经肌肉和呼吸损伤,在青春期变得更加明显。来自努那维克因纽特人队列的数据显示,该变异的等位基因频率(MAF)为0.03571,而一般人群的等位基因频率为0.00001341,这表明努那维克因纽特人群体中存在奠基人效应。我们的研究结果支持在努纳维克因纽特人群中存在与LCCS11相关的创始变异。我们的数据证实了其他报告,表明LCCS11不是普遍致命的,但长期幸存者有进行性神经肌肉损害的风险。在本报告中,我们还强调了与这种胎儿发病情况相关的重大产科并发症。
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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
432
审稿时长
2-4 weeks
期刊介绍: The American Journal of Medical Genetics - Part A (AJMG) gives you continuous coverage of all biological and medical aspects of genetic disorders and birth defects, as well as in-depth documentation of phenotype analysis within the current context of genotype/phenotype correlations. In addition to Part A , AJMG also publishes two other parts: Part B: Neuropsychiatric Genetics , covering experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. Part C: Seminars in Medical Genetics , guest-edited collections of thematic reviews of topical interest to the readership of AJMG .
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