Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.
- 作者列表："Monteiro FP","Curry CJ","Hevner R","Elliott S","Fisher JH","Turocy J","Dobyns WB","Costa LA","Freitas E","Kitajima JP","Kok F
:The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.
: Na +/K +-atp酶充当离子泵，在所有哺乳动物细胞类型中维持必需的质膜电位，并且对于许多细胞功能是必需的。有四种 α 亚型 (α1、 α2、 α3和 α4) 具有不同的表达模式、动力学性质和底物亲和力。Α2-亚型由ATP1A2编码，证据支持其在神经元的Cl-稳态以及出生时呼吸神经元的功能中至关重要。ATP1A2的单等位基因致病变异与家族性偏瘫性偏头痛2型 (FHM2) 和罕见的儿童交替性偏瘫1型 (AHC1) 相关。迄今为止，在人类中没有报道过双等位基因功能变体丧失的情况。然而，Atp1a2纯合功能缺失敲除小鼠 (α2-/-小鼠) 表现出严重的运动缺陷，缺乏自发运动，并且由于缺乏呼吸活动而导致围产期致死。在本报告中，我们描述了来自两个不相关家庭的三个新生儿，他们在新生儿中死亡，在子宫内表现为不寻常的胎儿水肿，癫痫发作和羊水过多。在出生时，他们有多个关节挛缩 (例如关节挛缩)，小头畸形，皮质发育畸形，畸形特征和严重的呼吸衰竭。全外显子组测序发现ATP1A2的双等位基因功能缺失变异，预测为致病。我们认为这是一种由Na +/K +-atp酶 α2亚型表达完全缺失引起的独特的新综合征。
METHODS:BACKGROUND:Thalassemia is one of the most common monogenetic diseases in the south of China and Southeast Asia. Hemoglobin Bart's hydrops fetalis syndrome was caused by a homozygous Southeast Asian deletion (-/-) in the HBA gene. Few studies have proved the potential of screen for Bart's hydrops fetalis using fetal cell-free DNA. However, the number of cases is still relatively small. Clinical trials of large samples would be needed. OBJECTIVE:In this study, we aimed to develop a noninvasive method of target-captured sequencing and genotyping by the Bayesian method using cell-free fetal DNA to identify the fetal genotype in pregnant women who are at risk of having hemoglobin Bart hydrops fetalis in a large-scale study. STUDY DESIGN:In total, 192,173 couples from 30 hospitals were enrolled in our study and 878 couples were recruited, among whom both the pregnant women and their husbands were detected to be carriers of Southeast Asian type (-/αα) of α-thalassemia. Prenatal diagnosis was performed by chorionic villus sampling, amniocentesis, or cordocentesis using gap-polymerase chain reaction considered as the golden standard. RESULTS:As a result, we found that the sensitivity and specificity of our noninvasive method were 98.81% and 94.72%, respectively, in the training set as well as 100% and 99.31%, respectively, in the testing set. Moreover, our method could identify all of 885 maternal samples with the Southeast Asian carrier and 36 trisomy samples with 100% of sensitivity in T13, T18, and T21 and 99.89% (1 of 917) and 99.88% (1 of 888) of specificity in T18 and T21, respectively. CONCLUSION:Our method opens the possibility of early screening for maternal genotyping of α-thalassemia, fetal aneuploidies in chromosomes 13/18/21, and hemoglobin Bart hydrops fetalis detection in 1 tube of maternal plasma.
METHODS:OBJECTIVES:Sickle cell disease (SCD) is a serious illness with disabling acute and chronic pain that needs better therapies, but insufficient patient participation in research is a major impediment to advancing SCD pain management. The purpose of this article is to discuss the challenges of conducting an SCD study and approaches to successfully overcoming those challenges. DESIGN:In a repeated-measures, longitudinal study designed to characterize SCD pain phenotypes, we recruited 311 adults of African ancestry. Adults with SCD completed 4 study visits 6 months apart, and age- and gender-matched healthy controls completed 1 visit. RESULTS:We recruited and completed measures on 186 patients with SCD and 125 healthy controls. We retained 151 patients with SCD with data at 4 time points over 18 months and 125 healthy controls (1 time point) but encountered many challenges in recruitment and study visit completion. Enrollment delays often arose from patients' difficulty in taking time from their complicated lives and frequent pain episodes. Once scheduled, participants with SCD cancelled 49% of visits often because of pain; controls canceled 30% of their scheduled visits. To facilitate recruitment and retention, we implemented a number of strategies that were invaluable in our success. CONCLUSION:Patients' struggles with illness, chronic pain, and their life situations resulted in many challenges to recruitment and completion of study visits. Important to overcoming challenges was gaining the trust of patients with SCD and a participant-centered approach. Early identification of potential problems allowed strategies to be instituted proactively, leading to success.
METHODS:OBJECTIVES:Sickle cell anemia is the commonest genetic disorder in India, and the frequency of the sickle cell gene is very high in the remote tribal areas where facilities are generally limited. Therefore, a rapid and affordable point-of-care test for sickle cell disease is needed. METHODS:The diagnostic accuracy of HemoTypeSC was evaluated against automated high-performance liquid chromatography (HPLC) as the gold standard for its efficacy in a newborn screening program. RESULTS:A total of 1,559 individuals (980 newborns and 579 adults) from four participating centers were analyzed by both methods. HemoTypeSC correctly identified 209 of 211 total hemoglobin (Hb) SS cases, for a 99.1%/99.9% total HbSS sensitivity/specificity. Overall, HemoTypeSC exhibited sensitivity and specificity of 98.1% and 99.1% for all possible phenotypes (HbAA, HbAS, and HbSS) detected. HPLC is relatively expensive and not available in most laboratories in remote tribal areas. CONCLUSIONS:We conclude that the rapid, point-of-care testing device HemoTypeSC test is suitable for population and newborn screening for the HbS phenotype.