Genetic, structural and clinical analysis of spastic paraplegia 4

Background: Spastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). Objective: To study genetic and clinical characteristics of SPG4 across Canada. Methods: The SPAST gene was analyzed in a total of 696 HSP patients from 431 families by either HSP-gene panel sequencing or whole exome sequencing (WES). We used Multiplex ligation-dependent probe amplification to analyze copy number variations (CNVs), and performed in silico structural analysis of selected mutations. Clinical characteristics of patients were assessed, and long-term follow-up was done to study genotype-phenotype correlations. Results: We identified 157 SPG4 patients from 65 families who carried 41 different SPAST mutations, six of which are novel and six are CNVs. We report novel aspects of mutations occurring in Arg499, a case with homozygous mutation, a family with probable compound heterozygous mutations, three patients with de novo mutations, three cases with pathogenic synonymous mutation, co-occurrence of SPG4 and multiple sclerosis, and novel or rarely reported signs and symptoms seen in SPG4 patients. Conclusion: Our study demonstrates that SPG4 is a heterogeneous type of HSP, with diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutation, pathogenic synonymous mutations and CNVs should be considered.

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Nagashima-Type Palmoplantar Keratosis: Clinical Characteristics, Genetic Characterization, and Clinical Management

BioMed Research International ◽

10.1155/2021/8841994 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Chao Huang ◽

Yali Yang ◽

Xingyu Huang ◽

Zongke Zhou

Keyword(s):

Clinical Management ◽

Clinical Characteristics ◽

Genetic Characterization ◽

Clinical Manifestations ◽

Compound Heterozygous ◽

Loss Of Function ◽

Gene Characterization ◽

Clade B ◽

Palmoplantar Keratosis ◽

Hands And Feet

Nagashima-type palmoplantar keratosis (NPPK) is the most prevalent palmoplantar keratoderma (PPK) in East Asia. Homozygous or compound heterozygous loss-of-function mutations in serpin peptidase inhibitor, clade B (ovalbumin), and member 70 (SERPINB7), which encodes members of the serine protease inhibitor superfamily, have been identified as the cause of NPPK. Clinical manifestations of NPPK include well-demarcated erythema, mild to moderate hyperkeratosis on the whole palm, and sole with transgrediens, extending to the dorsal surfaces of the hands and feet, inner wrists, ankles, and the Achilles tendon areas. In this study, we perform a review of relevant clinical cases aimed at elucidating the clinical characteristics, genetic characterization, differential diagnoses, and clinical management of NPPK. A better understanding of the clinical characteristics and pathogenic gene characterization of NPPK will enhance the diagnosis of NPPK, identify related diseases, and inform on the precise therapy and prognosis. Moreover, it will promote the awareness of NPPK in non-Asian regions.

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Clinical Characteristics of Pediatric Patients with Ocular Toxocariasis in China

Ophthalmologica ◽

10.1159/000443215 ◽

2016 ◽

Vol 235 (2) ◽

pp. 97-105 ◽

Cited By ~ 7

Author(s):

Yalu Liu ◽

Qi Zhang ◽

Jing Li ◽

Xunda Ji ◽

Yu Xu ◽

...

Keyword(s):

Rural Areas ◽

Clinical Characteristics ◽

Pediatric Patients ◽

Age Of Onset ◽

Age Groups ◽

Clinical Signs ◽

Clinical Manifestations ◽

Signs And Symptoms ◽

Enzyme Linked Immunosorbent Assay ◽

Ocular Toxocariasis

Objective: The aim of the study was to analyze the clinical characteristics of pediatric patients with ocular toxocariasis. Methods: Ocular toxocariasis was diagnosed and treated in 46 children from Shanghai and surrounding provinces. The diagnosis of ocular toxocariasis was confirmed immunologically by performing an enzyme-linked immunosorbent assay on serum and/or intraocular fluid. All pediatric patients and their guardians completed a questionnaire concerning their cases and living habits. Results: The mean age of onset was 6 ± 3 years. Most children (85%) resided in rural areas, and 91% of the children had contact with adult dogs or puppies. At the first visit, visual acuity (VA) was <20/200 in 36 cases, and we detected peripheral granuloma in 36 patients. In our study, the most common signs were vitritis, vitreous strands, and tractional retinal detachment. The Optomap 200Tx device detected granuloma with an 85% sensitivity, which is much higher than that of other techniques. We treated 40 cases (87%) with topical corticosteroids, while 28 patients (61%) were treated with systemic corticosteroids. Only 18 children (39%) required surgical intervention. All patients were examined and treated by the same ophthalmologists. Conclusions: Preschool children in China are more often affected by toxocariasis compared with other age groups. The most common signs included unilateral granuloma and ocular inflammation. In our study, clinical manifestations were severe and complicated. At the first visit, VA was <20/200 in most patients. Ocular toxocariasis was diagnosed on the basis of clinical signs and symptoms; the diagnosis was confirmed by immunological testing. Techniques using the Optomap 200Tx device can facilitate the early detection and lead to better visual prognosis.

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Identification of Novel Mutations inABCA4Gene: Clinical and Genetic Analysis of Indian Patients with Stargardt Disease

BioMed Research International ◽

10.1155/2015/940864 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

Rajani Battu ◽

Anshuman Verma ◽

Ramesh Hariharan ◽

Shuba Krishna ◽

Ravi Kiran ◽

...

Keyword(s):

Genetic Analysis ◽

Vision Loss ◽

Variant Calling ◽

Signs And Symptoms ◽

Cost Effective ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Stargardt Disease ◽

Indian Patients ◽

Targeted Gene Sequencing

Stargardt disease (STGD) is the leading cause of juvenile macular degeneration associated with progressive central vision loss, photophobia, and colour vision abnormalities. In this study, we have described the clinical and genetic features of Stargardt patients from an Indian cohort. The next generation sequencing was carried out in five clinically confirmed unrelated patients and their family members using a gene panel comprising 184 retinal specific genes. Sequencing results were analyzed by read mapping and variant calling in genes of interest, followed by their verification and interpretation. Genetic analysis revealedABCA4mutations in all of the five unrelated patients. Among these, four patients were found with compound heterozygous mutations and another one had homozygous mutation. All the affected individuals showed signs and symptoms consistent with the disease phenotype. We report two novelABCA4mutations in Indian patients with STGD disease, which expands the existing spectrum of disease-causing variants and the understanding of phenotypic and genotypic correlations. Screening for causative mutations in patients with STGD using panel of targeted gene sequencing by NGS would be a cost effective tool, might be helpful in confirming the precise diagnosis, and contributes towards the genetic counselling of asymptomatic carriers and isolated patients.

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Whole-exome sequencing of de novo genetic variants in a Chinese family with a sporadic case of congenital nonsyndromic hearing loss

F1000Research ◽

10.12688/f1000research.27739.1 ◽

2021 ◽

Vol 10 ◽

pp. 61

Author(s):

Sijing Hu ◽

Hao Zhang ◽

Yunqiang Liu ◽

Mohan Liu ◽

Jingjing Li ◽

...

Keyword(s):

Hearing Loss ◽

Genetic Variants ◽

Cellular Localization ◽

De Novo ◽

Copy Number Variations ◽

Occurrence Rate ◽

Chinese Family ◽

Compound Heterozygous ◽

Functional Assay ◽

Whole Exome

Background: We examined the genetic variants of a Chinese family with a 22-month-old infant with sporadic non-syndromic sensorineural hearing loss (NSHL). Methods: The whole-exome sequence data in the family, especially the de novo variants presented in the patient, were analyzed and the effect of the disease-causing genetic variants on the protein expression level and cellular localization were examined by cell-based functional assay. Results: The infant had no known NSHL-causing variants, except two compound heterozygous variants in connexin26 gene GJB2; one was the c.79G>A, c.341A>G haplotype from the asymptomatic mother which was benign, and the other was a de novo pathogenic c.262G>C (p.A88P). In vitro, GJB2 with c.262G>C was weakly expressed and displayed a punctate distribution in the cytoplasm and cytomembrane, while wild type GJB2 was robustly expressed in the cytomembrane. We deduced that the de novo pathogenic GJB2 c.262G>C exacerbated loss-of-function in the context of leaky variants c.79G>A, c.341A>G in the patient. Interestingly, further analysis of exome sequences revealed that the occurrence of de novo pathogenic variants in the infant was frequent. Among the total~47,000 variants, 143 were de novo in the patient, whereas among all 74 variants predicted to be pathogenic/likely pathogenic, 21 were heterozygous and two were homozygous de novo. The occurrence rate of de novo deleterious variants was much higher (31.1%, 23/74) than that in total (0.34%, 143/47,000). It is notable that most genes with de novo deleterious variants were environment-sensitive, such as GJB2, MNK1, MNK2, MUC4, RAD21 and DNA copy number variations. Conclusions: The full picture of genetic variants in the exome might help us to interpret the NSHL-causing variants. More research is needed into the causes of de novo deleterious variants and gene-environment interactions in congenital NSHL.

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Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica’s experience

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-02162-z ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

R. Badilla-Porras ◽

A. Echeverri-McCandless ◽

J. M. Weimer ◽

A. Ulate-Campos ◽

A. Soto-Rodríguez ◽

...

Keyword(s):

Clinical Diagnosis ◽

Clinical Characteristics ◽

Clinical Manifestations ◽

Cerebellar Atrophy ◽

Batten Disease ◽

Costa Rican ◽

Common Element ◽

Neuronal Ceroid Lipofuscinoses ◽

Molecular Testing ◽

Homozygous Mutation

Abstract Background Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G > T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population. Objective To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to characterize via molecular testing their causative mutations. Methods DNA extracted from buccal swabs was used for CLN6 gene sequencing. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records. Results Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens. Conclusions This investigation supports that the previously characterized c.214G > T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

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Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries

Circulation Research ◽

10.1161/circresaha.119.315821 ◽

2020 ◽

Vol 126 (7) ◽

pp. 811-821 ◽

Cited By ~ 5

Author(s):

Xuanyu Liu ◽

Wen Chen ◽

Wenke Li ◽

James R. Priest ◽

Yuanyuan Fu ◽

...

Keyword(s):

Candidate Genes ◽

Clinical Characteristics ◽

Congenital Heart ◽

De Novo ◽

Ductus Arteriosus ◽

Compound Heterozygous ◽

Control Analysis ◽

Pathogenic Role ◽

Polygenic Inheritance

Rationale: Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases. Understanding the clinical characteristics and pathogenesis of TGA is, therefore, urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic cause underlying TGA remain largely unexplored. Objective: We sought to systematically examine the clinical characteristics and genetic cause for isolated nonsyndromic TGA. Methods and Results: We recruited 249 patients with TGA (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in patients with TGA. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous, or X-linked recessive variants. Established congenital heart disease–causing genes, such as FOXH1 , were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had >1 candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance. Conclusions: The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.

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Clinical Characteristics and Gene Mutation Analysis of the Chinese Han Population with Gitelman Syndrome: 3 Case Reports and a Literature Review

Case Reports in Medicine ◽

10.1155/2020/6263721 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Xueting Li ◽

Ruofei Chen ◽

Mingwei Chen

Keyword(s):

Gene Mutation ◽

Mutation Analysis ◽

Clinical Characteristics ◽

Clinical Phenotype ◽

Gene Mutations ◽

Gitelman Syndrome ◽

Chinese Patients ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Gene Mutation Analysis

The present study reported clinical characteristics and the results of gene mutation analysis of 3 Chinese patients with Gitelman syndrome (GS). Three patients manifested with normal blood pressure, recurrent hypokalemia, and metabolic alkalosis. Only case 2 had obvious hypomagnesemia. Gene sequencing showed a compound heterozygous mutation in SCL12A3 in case 1 and a homozygous mutation in SCL12A3 in case 2. Heterozygous mutations in SCL12A3 and CLCNKB were found in case 3. Then, the literature was reviewed. The keyword “Gitelman syndrome” was inputted into the PubMed, Wanfang Database, and CNK to search all Chinese patients with GS diagnosed by gene mutations and to extract complete clinical data from December 1998 to 2018. Finally, a total of 124 cases of GS were included. No significant differences in the levels of serum potassium and magnesium were observed among the different gene mutations, and the serum magnesium levels in adults were lower than those of the juvenile. GS with reduced blood magnesium had a serious clinical phenotype. Therefore, GS had a diverse phenotype, and its final diagnosis required genetic profiling. The relationship of gene mutation and clinical phenotype needed further study.

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Clinical Characteristics of Inpatients with Anaphylaxis in China

BioMed Research International ◽

10.1155/2015/429534 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Rui Tang ◽

Han-Yi Xu ◽

Ju Cao ◽

Shi Chen ◽

Jin-Lu Sun ◽

...

Keyword(s):

Clinical Characteristics ◽

Clinical Manifestations ◽

Signs And Symptoms ◽

Multiple Organ ◽

Female Ratio ◽

Multisystem Involvement ◽

Organ Systems ◽

Number Of Patients ◽

Male Patients ◽

Male To Female

Objective.To analyze the clinical characteristics of inpatients with anaphylaxis and the factors that influenced those characteristics.Methods.Using the patient records from 1990 to 2013 from three highly ranked Chinese hospitals, we retrospectively analyzed the characteristics of 108 inpatients with anaphylaxis (not anaphylaxis admitted).Results.The mean patient age was42±20years old and male-to-female ratio was 1 : 1.3. The number of patients with anaphylaxis increased gradually, and cases diagnosed after 2005 accounted for 68.5% of the 108 total cases. The most common trigger was medications. The most common clinical manifestations included cutaneous, nervous, respiratory, circulatory, and digestive signs and symptoms. Male patients were more likely to experience loss of consciousness. Multisystem involvement was more likely to develop in patients with low BP, whereas it was uncommon in those with anaphylaxis induced by antibiotics or anesthetics. Epinephrine was used as the first-line treatment for 56 cases.Conclusions.Inpatient with anaphylaxis was more common in female patients and the number increased gradually during the study period. The most common trigger was medications. Patients with low BP were prone to having multisystem involvement, whereas the cases of anaphylaxis induced by antibiotics and anesthetics were less likely to involve multiple organ systems.

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Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) Clinical Findings and Molecular Diagnosis: Costa Rica´s Experience

10.21203/rs.3.rs-860956/v1 ◽

2021 ◽

Author(s):

Ramses Badilla-Porras ◽

Ann Echeverri-McCandless ◽

Jill Weiner ◽

Adriana Ulate-Campos ◽

Andrés Soto-Rodríguez ◽

...

Keyword(s):

Costa Rica ◽

Clinical Diagnosis ◽

Clinical Characteristics ◽

Clinical Manifestations ◽

Cerebellar Atrophy ◽

Batten Disease ◽

Costa Rican ◽

Common Element ◽

Neuronal Ceroid Lipofuscinoses ◽

Homozygous Mutation

Abstract Background: Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G>T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population.Objective: To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to genetically characterize their causative mutations.Methods: CLN6 gene sequences were determined from DNA extracted from patient buccal swabs. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records.Results: Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously-described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens.Conclusions: This investigation supports that the previously characterized c.214G>T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

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Rare novel LPL mutations are associated with neonatal onset lipoprotein lipase (LPL) deficiency in two cases

BMC Pediatrics ◽

10.1186/s12887-021-02875-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yun Qin Wu ◽

Yue Yuan Hu ◽

Gui Nan Li

Keyword(s):

Lipid Metabolism ◽

Lipoprotein Lipase ◽

Clinical Manifestations ◽

Recurrent Infection ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Genetic Characteristics ◽

Neonatal Onset

Abstract Background Lipoprotein lipase (LPL) deficiency is a monogenic lipid metabolism disorder biochemically characterized by hypertriglyceridemia (HTG) inherited in an autosomal recessive manner. Neonatal onset LPL deficiency is rare. The purpose of this study was to clarify the clinical features of neonatal LPL deficiency and to analyze the genetic characteristics of LPL gene. Methods In order to reach a definite molecular diagnose, metabolic diseases-related genes were sequenced through gene capture and next generation sequencing. Meanwhile, the clinical characteristics and follow-up results of the two newborns were collected and analyzed. Results Three different mutations in the LPL gene were identified in the two newborns including a novel compound heterozygous mutation (c.347G > C and c.472 T > G) and a reported homozygous mutation (c.836 T > G) was identified. Interestingly, both the two neonatal onset LPL deficiency patients presented with suffered recurrent infection in the hyperlipidemia stage, which was not usually found in childhood or adulthood onset LPL deficiency patients. Conclusion The two novel mutaitons, c.347G > C and c.472 T > G, identified in this study were novel, which expanded the LPL gene mutation spectrum. In addition, suffered recurrent infection in the hyperlipidemia stage implied a certain correlation between immune deficiency and lipid metabolism abnormality. This observation further supplemented and expanded the clinical manifestations of LPL deficiency.

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