Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.
- 作者列表："Hughes JJ","Alkhunaizi E","Kruszka P","Pyle LC","Grange DK","Berger SI","Payne KK","Masser-Frye D","Hu T","Christie MR","Clegg NJ","Everson JL","Martinez AF","Walsh LE","Bedoukian E","Jones MC","Harris CJ","Riedhammer KM","Choukair D","Fechner PY","Rutter MM","Hufnagel SB","Roifman M","Kletter GB","Delot E","Vilain E","Lipinski RJ","Vezina CM","Muenke M","Chitayat D
:In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
: 在两个独立的正在进行的前脑无裂畸形个体和性发育障碍个体的下一代测序项目中，并通过国际研究合作，我们在蛋白磷酸酶 1，调节亚基 1 2a (PPP 1R 1 2A) 中鉴定了 12 个具有新生功能丧失 (LoF) 变异体的个体，参与细胞迁移、粘附的重要发育基因，和形态发生。该基因以前没有与人类疾病相关的报道，它对LoF不耐受，gnomAD中观察到的LoF变异与预期的比率非常低。在 12 例个体中，5 例发现中线脑畸形，9 例发现泌尿生殖系统畸形，2 例发现两种表型的组合。其他确定的先天性异常包括脐膨出、空肠和回肠闭锁伴肠系膜血供异常和并指。6 个个体有停止增益变异体，5 个个体有缺失或重复导致移码，1 个个体有规范的剪接受体位点丢失。鼠和人原位杂交和免疫染色发现PPP1R12A在前脑分裂和泌尿生殖发育的关键时期在前脑神经皱褶中表达，在下尿路中蛋白定位。基于这些临床和分子研究结果，我们提出了PPP1R12A致病变异与影响大脑和泌尿生殖系统胚胎发生的先天性畸形综合征的关联，包括性发育障碍。
METHODS::Impairments in social cognition have been frequently described in 22q11.2 deletion syndrome (22q11.2DS) and are thought to be a hallmark of difficulties in social interactions. The present study addresses aspects that are critical for everyday social cognitive functioning but have received little attention so far. Sixteen children with 22q11.2DS and 22 controls completed 1 task of facial expression recognition, 1 task of attribution of facial expressions to faceless characters involved in visually presented social interactions, and 1 task of attribution of facial expressions to characters involved in aurally presented dialogues. All three tasks have in common to involve processing of emotions. All participants also completed two tasks of attention and two tasks of visual spatial perception, and their parents completed some scales regarding behavioural problems of their children. Patients performed worse than controls in all three tasks of emotion processing, and even worse in the second and third tasks. However, they performed above chance level in all three tasks, and the results were independent of IQ, age and gender. The analysis of error patterns suggests that patients tend to coarsely categorize situations as either attractive or repulsive and also that they have difficulties in differentiating emotions that are associated with threats. An isolated association between the tasks of emotion and behaviour was found, showing that the more frequently patients with 22q11.2DS perceive happiness where there is not, the less they exhibit aggressive behaviour.
METHODS:BACKGROUND:We describe the first radiographic clinic in the literature for DDH and how this novel clinic can significantly improve the efficiency and cost-effectiveness of service in a tertiary referral centre. AIMS:A radiographic clinic for the management of developmental dysplasia of the hip was introduced in 2017 in our institution. We performed a detailed cost analysis to assess the economic savings made with the introduction of this new clinic. We assessed the efficiency of the service by identifying how many unnecessary outpatient visits were prevented. We also assessed the difference in times from referral to review between the two clinics. METHODS:Analysis of the clinic activity in 2017 was possible as all data was collected prospectively by the DDH CNS and stored in our database. Cost analysis was performed, and the savings made per patient along with the financial benefit to our institution was recorded. RESULTS:The new radiographic clinic reduced the cost of reviewing one patient by €162.51 per patient. There was a 73% discharge rate from the clinic which prevented 251 unnecessary patient visits to the outpatient department over the course of the year. There was a significant 11-day reduction in waiting times between referral and review when comparing the radiographic to the conventional clinic (p < 0.05). CONCLUSIONS:A radiographic clinic for the management of developmental dysplasia of the hip has a significant effect on the efficiency and overall cost-effectiveness of service provision in a tertiary referral centre.
METHODS:INTRODUCTION:Triple pelvic osteotomy (TPO) involves periacetabular osteotomies of the ilium, ischium, and pubis to reorient the acetabulum. This operation is indicated in certain situations for the treatment of developmental dysplasia of the hip, dysplastic neuromuscular hips, and for containment of the femoral head in cases of Legg-Calvé-Perthes disease. METHODS:This retrospective cohort study compares radiographic outcomes of patients who underwent TPO using two different techniques and describes a novel single-incision direct lateral approach. TPO was performed on 22 patients by the senior author. The first 10 patients underwent TPO through a single-incision anterolateral approach. The last 12 patients underwent TPO using the direct lateral approach. Preoperative and postoperative pelvic radiographs were reviewed for each patient, and the migration index and center-edge angle were recorded. RESULTS:The migration index and center-edge angle were evaluated and were not found to be significantly different between the anterolateral and direct lateral groups. The direct lateral approach is described. CONCLUSION:The direct lateral approach for TPO is equivalent to the anterolateral approach on radiographic evaluation. Advantages of the direct lateral approach include direct visualization of the ischial osteotomy, effective mobilization of the acetabulum, and safety of the sciatic nerve.