Identification of a de novo CACNA1B variant and a start-loss ADRA2B variant in paroxysmal kinesigenic dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) represents the most prevalent form of paroxysmal dyskinesia, characterized by recurrent and transient attacks of involuntary movements triggered by a sudden voluntary action. In this study, whole-exome sequencing was conducted on a cohort of Chinese patients to identify causal mutations. In one young female case, a de novo CACNA1B variant (NM_000718.3:exon3:c.479C > T:p.S160F) was identified as the causative lesion. This finding may broaden the phenotypic spectrum of CACNA1B mutations and provide a prospective cause of primary PKD. Additionally, a novel start-loss variant (NM_000682.7:c.3G > A) within ADRA2B further denied its association with benign adult familial myoclonic epilepsy, and a KCNQ2 E515D variant that was reported as a genetic susceptibility factor for seizures had no damaging effect in this family. In sum, this study established a correlation between CACNA1B and primary PKD, and found valid evidence that further negates the pathogenic role of ADRA2B in benign adult familial myoclonic epilepsy.

A missense variant in MYOF is associated with ARVC and sudden cardiac death.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is rare autosomal dominant genetic disorder that leads to severe arrhythmia and sudden cardiac death. Although previous studies in clinical, pathological and genetics of ARVC established consensus diagnostic criteria and expanded the spectrum of pathogenic genes, there is still a proportion of patients with unclear causative factors. Here, whole-exome sequencing was employed to investigate the genetic etiology of a 15-year-old sudden cardiac death female caused by ARVC. A novel variant of MYOF (NM_013451.3: c.4723G > C: p.D1575H) was identified, which is a member of the Ferlin family of proteins is associated with cardiomyopathy. And the bioinformatics analysis predicted the pathogenicity of this variant. We report the first variant of MYOF in ARVC, which imply a vital role of MYOF in cardiomyopathy.

Whole-exome sequencing detected a novel AIFM1 variant in a Han-Chinese family with Cowchock syndrome.

Charcot-Marie-Tooth disease(CMT) is a hereditary peripheral neuropathy, characterized by progressive distal hypoesthesia and amyotrophia. CMT is characterized by an X- linked recessive inheritance pattern. The apoptosis-inducing factor mitochondria associated-1 (AIFM1) is the main pathogenic gene of the X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4), also known as Cowchock syndrome. In this study, we enrolled a family with CMTX from the southeast region of China and identified a novel AIFM1 variant (NM_004208.3: c.931C>G; p.L311V) using whole exon sequencing technology. The results of our study may also be useful for genetic counseling, embryo screening of in vitro fertilization embryos, and prenatal genetic diagnosis.

A novel nonsense PKD1L1 variant cause heterotaxy syndrome with congenital asplenia in a Han Chinese patient.

Heterotaxy syndrome is a very rare congenital disease, which is caused by the disorder of left-right asymmetry during visceral development. However, pathogenic genetic lesions are found in less than 20% of HS patients. In this cohort study, whole-exome sequencing was performed for 110 patients with situs inversus or situs ambiguous. We identified a novel nonsense variant in PKD1L1(c.1387 C > T; p.463Gln*) in a Chinese patient with heterotaxy syndrome and congenital asplenia. This homozygous variant caused the domain of PKD1L1 complete absence. To our knowledge, this novel variant is the first phenotype of congenital asplenia found in patients with PKD1L1 variants, and the first PKD1L1 variant found in China. Our findings expand the spectrum of PKD1L1 variants and provide support for PKD1L1 variant and congenital asplenia, and the critical role of PKD1L1 during left-right patterning in the Han Chinese population.

Case Report: BAF-Opathies/SSRIDDs Due to a de novo ACTL6A Variant, Previously Considered to Be Heart-Hand Syndrome.

Purpose: This study aims to identify genetic lesions in patients with congenital heart disease (CHD) with or without other phenotypes. In this study, over 400 patients were recruited and several novel variants in known causative genes were identified. A Chinese patient clinically diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) was included in the study cohort. Methods: Targeted, whole exome, and Sanger sequencing were performed to identify genetic lesions. The effects of the variant on ACTL6A RNA and protein were assessed using bioinformatics analysis. Results: At the start of the study, no mutations in known and candidate causative genes associated with CHD were identified. Seven years later, we noticed craniofacial deformities and identified a de novo heterozygous deletion variant in ACTL6A (NM_004301, c.478_478delT; p.F160Lfs*9). Intellectual disability and short stature were identified by a follow-up visit 10 years later. This variant leads to frameshift sequences and a premature termination codon and may affect the features of proteins. According to the nonsense-mediated mRNA decay theory, this variant may induce the decay of ACTL6A mRNA in patients. Conclusion: Our study reported the first ACTL6A variant in a Chinese individual, providing further evidence that ACTL6A is involved in heart and upper limb skeletal and intellectual development, thereby expanding the spectrum of ACTL6A variants. Thus, mutation analysis of the ACTL6A gene should be considered in patients with BAF-opathies or heart-hand syndromes due to potential misdiagnosis. Craniofacial dysmorphisms and intellectual disability are key to distinguishing these two diseases clinically, and attention to developmental delay/intellectual disability and craniofacial deformities will contribute to the diagnosis of BAF-opathies.

Case Report: Mutant SCN9A Susceptible to Charcot Neuroarthropathy in a Patient With Congenital Insensitivity to Pain.

Charcot neuroarthropathy is a systemic disease with pathological changes in the musculoskeletal system, which leads to fractures, dislocations, and deformities involving multiple bones and joints, particularly those of the feet. While the common underlying cause of Charcot neuroarthropathy is diabetes mellitus, it is also associated with congenital insensitivity to pain (CIP). CIP is a rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. In this study, we report a patient with CIP from a consanguineous family susceptible to Charcot neuroarthropathy with a novel SCN9A mutation. This report involves the case of a middle-aged man who suffered from CIP, had repeated painless fractures, and developed bone and joint destruction. The physical and radiological examinations revealed that multiple joints were swollen and deformed, and soft-tissue trauma was evident. We identified a novel homozygous SCN9A mutation (p.Cys1339Arg) by whole-exome sequencing (WES), which was verified using Sanger sequencing. In addition, the wild-type (WT) and mutated p. Cys1339Arg were assessed in HEK293 cells expressing Nav1.7, and the results showed that p. Cys1339Arg almost abolished the Nav1.7 sodium current. In conclusion, Charcot neuroarthropathy associated with CIP demonstrated a wider spectrum of Charcot neuroarthropathy than was previously recognized or documented. In addition, this finding is conducive to understanding the critical amino acids for maintaining the function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.

A novel POF1B variant in a Chinese patient is associated with premature ovarian failure.

A novel mutation of POF1B was identified in a patient with premature ovarian failure.

A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia.

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

A Novel Nonsense MMP21 Variant Causes Dextrocardia and Congenital Heart Disease in a Han Chinese Patient.

The position and morphology of human internal organs are asymmetrically distributed along the left-right axis. Aberrant left-right patterning in the developing embryo can lead to a series of congenital laterality defects, such as dextrocardia and heterotaxy syndrome. Laterality defects are a genetic condition; however, pathogenic genetic lesions are found in only one-fifth of patients. In this study, whole-exome sequencing was conducted for 78 patients with laterality defects. We identified a novel stopgain variant in MMP21 (c.G496T; p.G166*) in a Chinese patient with mirror-image dextrocardia. This variant caused a truncated MMP21 mRNA containing only the signal peptide and propeptide, while the coding sequence of matrix metalloproteinase-21 was almost entirely absent. To the best of our knowledge, this novel variant is the first homozygous stopgain variant identified in dextrocardia patients, and the first MMP21 variant found in East Asia. Our findings expand the spectrum of MMP21 variants and provide support for the critical role of MMP21 during left-right patterning in the Han Chinese population.

Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism.

Proximal symphalangism (SYM1) is an autosomal dominant disorder manifested by ankylosis of the proximal interphalangeal joints of fingers, carpal and tarsal bone fusion, and conductive hearing loss in some cases. Herein, we clinically diagnosed a Chinese patient with fusions of the bilateral proximal interphalangeal joints in the 2-5 digits without conductive hearing loss. Family history investigation revealed that his mother and grandfather also suffered from SYM1. Whole exome sequencing was performed to detect the genetic lesion of the family. The candidate gene variants were validated by Sanger sequencing. By data filtering, co-segregation analysis and bioinformatics analysis, we highly suspected that an unknown heterozygous frameshift variant (c.635_636insG, p.Q213Pfs*57) in NOG was responsible for the SYM1 in the family. This variant was predicted to be deleterious and resulted in a prolonged protein. This finding broadened the spectrum of NOG mutations associated with SYM1 and contributed to genetic diagnosis and counseling of families with SYM1.

Novel Compound Heterozygous DST Variants Causing Hereditary Sensory and Autonomic Neuropathies VI in Twins of a Chinese Family.

Background: Hereditary sensory and autonomic neuropathies (HSANs) are a rare and severe group of sensory axonal neuropathies. HSANs have been classified into eight groups based on mode of inheritance, clinical features, and the involved genes. HSAN-VI, perhaps the most notable type, is an autosomal recessive disease, which manifests as the severely impaired pain sensitivity, autonomic disturbances, distal myopathy, spontaneous or surgical amputations, and sometimes early death. Mutations in DST have been identified as the cause of HSAN-VI. DST encodes dystonin, a member of the plakin protein family that is involved in cytoskeletal filament networks. Dystonin has seven major isoforms in nerve, muscle, and epithelium. Material and Methods: The present study investigated a Chinese family with HSAN and explored potential pathogenic variants using whole-exome sequencing (WES). Variants were screened and filtered through bioinformatics analysis and prediction of variant pathogenicity. Co-segregation analysis was subsequently conducted. Results: We identified compound heterozygous variants of DST (c.3304G>A, p.V1102I and c.13796G>A, p.R4599H) in two patients. Conclusion: We reported on a Chinese family with HSAN-VI family and detected the disease-causing variants. Our description expands the spectrum of known DST variants and contributes to the clinical diagnosis of HSAN-VI.

Exome sequencing identifies a novel nonsense mutation of Ring Finger Protein 207 in a Chinese family with Long QT syndrome and syncope.

Long QT syndrome (LQTS) is a rare inherited arrhythmia disease characterized by a prolonged QT interval on 12-lead electrocardiograms. It is the crucial factor to induce syncope, ventricular fibrillation, and even sudden cardiac death. Previous studies have proved that mutations of ion channels-related genes play an important role in LQTS patients. In this study, we enrolled a Chinese family with LQTS and syncope. With the help of whole-exome sequencing, we identified a novel nonsense mutation (c.439C>T/p.Q147X) of Ring Finger Protein 207 (RNF207) in this family. The novel mutation, resulting in a premature stop codon in exon 4 of the RNF207 gene, co-segregated with the affected individuals. Bioinformatics analysis and real-time PCR further proved that the newly identified mutation might induce nonsense-mediated mRNA decay. In mutation carriers, the level of RNF207 mRNA expression was much lower than controls, which may affect potassium channel KCNH2 and lead to LQTS and syncope. In this research, we reported a rare novel mutation of RNF207 in LQTS and syncope patients which further supports the significant role of RNF207 in potassium channel activation and expanded the spectrum of RNF207 mutations. These data may contribute to the genetic diagnosis and counseling of families with LQTS and syncope.