Filamin B:The next hotspot in skeletal research?

Filamin B （FLNB） is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Lip to present, pathogenic mutations in FLNB are solely found to cause skeletal deformities, indicating the important role of FLNB in skeletal development. FLNB-related disorders are classified as spondylocarpotarsal synostosis （SCT）, Larsen syndrome （LS）, atelosteogenesis （AO）, boomerang dysplasia （BD）, and isolated congenital talipes equinovarus, presenting with scoliosis, short- limbed dwarfism, clubfoot, joint dislocation and other unique skeletal abnormalities. Several mecha- nisms of FLNB mutations causing skeletal malformations have been proposed, including delay of ossi- fication in long bone growth plate, reduction of bone mineral density （BMD）, dysregulation of muscle differentiation, ossification of intervertebral disc （IVD）, disturbance of proliferation, differentiation and apoptosis in chondrocytes, impairment of angiogenesis, and hypomotility of osteoblast, chondrocyte and fibroblast. Interventions on FLNB-related diseases require prenatal surveillance by sonography, gene testing in high-risk carriers, and proper orthosis or orthopedic surgeries to correct malformations including scoliosis, cervical spine instability, large joint dislocation, and clubfoot. Gene and cell therapies for FLNB-related diseases are also promising but require further studies.

Mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation

Background:Brain arteriovenous malformations(BAVMs)are abnormal vessels that are apt to rupture,causing lifethreatening intracranial hemorrhage(ICH).The estimated prevalence of BAVMs is 0.05%among otherwise healthy individuals.In this study,we aim to investigate the mutational spectrum of syndromic genes in sporadic BAVM.Methods:We recruited a cohort of 150 patients with BAVM and performed whole-exome sequencing on their peripheral blood DNA.To explore the mutational spectrum of syndromic genes in sporadic brain arteriovenous malformation,we selected six genes according to the Online Mendelian Inheritance in Man(OMIM)and literature.All variants in the six candidate genes were extracted and underwent filtering for qualifying variants.Results:There are a total of four patients with rare variants in hereditary hemorrhagic telangiectasia-related genes.In addition,we identified two patients have the variant of RASA1 gene in our database,which are also rare mutations that are absent from population databases.However,we did not find any patients with GNAQ mutations in our database.Conclusions:In conclusion,we demonstrated that variants in syndromic vascular malformations play important roles in the etiology of sporadic BAVM.

Recent Advances in Technique and Clinical Outcomes of Minimally Invasive Spine Surgery in Adult Scoliosis

Objective： Conventional open spinal surgery of adult scoliosis can be performed from anterior, posterior, or combined approach. Minimally invasive spine surgery （MISS） was developed for the purpose of reducing the undesirable effects and complications. This review aimed to make a brief summary of recent studies of the approach and clinical outcomes of MISS in adult scoliosis. Data Sources： We conducted a systematic search from PubMed, Medline, EMBASE, and other literature databases to collect reports of surgical methods and clinical outcomes of MISS in treatment of adult scoliosis. Those reports were published up to March 2017 with the following key terms： ＆quot;minimally invasive,＆quot; ＆quot;spine,＆quot; ＆quot;surgery,＆quot; and ＆quot;scoliosis.＆quot;Study Selection： The inclusion criteria of the articles were as followings： diagnosed with adult degenerative scoliosis （DS） or adult idiopathic scoliosis; underwent MISS or open surgery; with follow-up data. The articles involving patients with congenital scoliosis or unknown type were excluded and those without any follow-up data were also excluded from the study. The initial search yielded 233 articles. After title and abstract extraction, 29 English articles were selected for full-text review. Of those, 20 studies with 831 patients diagnosed with adult DS or adult idiopathic scoliosis were reviewed. Seventeen were retrospective studies, and three were prospective studies. Results： The surgical technique reported in these articles was direct or extreme lateral interbody fusion, axial lumbar interbody fusion, and transforaminal lumbar interbody fusion. Among the clinical outcomes of these studies, the operated levels was 3–7, operative time was 2.3–8.5 h. Both the Cobb angle of coronal major curve and evaluation of Oswestry Disability Index and Visual Analog Scale decreased after surgery. There were 323 complications reported in the 831 （38.9%） patients, including 150 （18.1%） motor or sensory deficits, and 111 （13.4%） implant-related complications. Conclusions： MISS can provide good radiological and self-evaluation improvement in treatment of adult scoliosis. More prospective studies will be needed before it is widely used.

Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.

The identification of PAX7 variants and a potential role of muscle development dysfunction in congenital scoliosis

Dear Editor,Congenital scoliosis(CS)is a spinal malformation charac-terized by failure of vertebral formation or segmentation,or a mix of these deformities,resulting in longitudinal and rotational imbalance,and affects 0.05-0.1%of new-borns(Wu et al.2015).It is generally understood that the development of CS has an underlying genetic basis.Specifically,genes related to somite regulation or osteo-genesis during embryonic development are believed to be responsible for the vertebral malformations observed in CS patients(Pourquie 2011).

Advances in clinical genetics and genomics

Developments in genetics and genomics are progressing at an unprecedented speed.Twenty years ago,the human genome project provided the first glimpses into the human genome sequence and launched a new era of human genetics.The emerging of next-generation sequencing(NGS)in 2005 then made possible comprehensive genetic testing such as exome sequencing and genome sequencing.Meanwhile,great efforts have been put into the optimization of bioinformatic pipelines to make increasingly speedy and accurate variant analyses based on NGS data.These advances in sequencing technologies and analytical methods have revolutionized the diagnostic odyssey of suspected hereditary diseases.More recently,the genotype-phenotype relationship and polygenic risk scores(PRSs)generated from genome-wide association studies have expanded our horizon from rare genetic mutations to a genomic landscape implicated by the combined effect of both rare variants and polymorphisms.At the same time,clinicians and genetic counselors are facing huge challenges conferred by overwhelming genomic knowledge and long sheets of testing reports for comprehensive genomic sequencing.The path toward the“next-generation”clinical genetics and genomics may underlie semiautomatic pipelines assisted by artificial intelligence techniques.