Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Abstract Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

Download Full-text

Practical guide to genetic screening for inherited eye diseases

Therapeutic Advances in Ophthalmology ◽

10.1177/2515841420954592 ◽

2020 ◽

Vol 12 ◽

pp. 251584142095459

Author(s):

Cécile Méjécase ◽

Samantha Malka ◽

Zeyu Guan ◽

Amy Slater ◽

Gavin Arno ◽

...

Keyword(s):

Genetic Screening ◽

Treatment Options ◽

Genomic Medicine ◽

Genetic Diagnosis ◽

Eye Diseases ◽

Practical Guide ◽

Whole Exome ◽

Post Test ◽

Pros And Cons ◽

Gene Panels

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.

Download Full-text

CAPN1 Variants as Cause of Hereditary Spastic Paraplegia Type 76

Case Reports in Neurological Medicine ◽

10.1155/2019/7615605 ◽

2019 ◽

Vol 2019 ◽

pp. 1-5

Author(s):

Jesus Eduardo Garcia-Berlanga ◽

Mariana Moscovich ◽

Isaac Jair Palacios ◽

Alejandro Banegas-Lagos ◽

Augusto Rojas-Martinez ◽

...

Keyword(s):

Autosomal Recessive ◽

Brain Mri ◽

Young Female ◽

Sequencing Analysis ◽

Spastic Paraplegia ◽

Case Presentation ◽

Significant Family History ◽

Hereditary Spastic Paraplegias ◽

Whole Exome ◽

Oculomotor Abnormalities

Background. Autosomal recessive hereditary spastic paraplegias (HSP) are a rare group of hereditary neurodegenerative disorders characterized by spasticity with or without other symptoms. SPG11 gene is the most common cause of autosomal recessive HSP. We report a case of autosomal recessive spastic paraplegia type 76 due to heterozygous variants of CAPN1 in an Argentinean subject. Case Presentation. A 38-year-old Argentinean female presented with progressive gait problems and instability of 15-year duration. Oculomotor abnormalities, ataxia, bradykinesia, cervical dystonia, and lower limb pyramidal signs were observed. Brain MRI was unremarkable. Whole-exome sequencing analysis identified two heterozygous variants in CAPN1. Conclusions. Clinicians should screen for CAPN1 mutation in a young female patient without significant family history with a spastic paraplegia syndrome associated with other symptoms.

Download Full-text

Genetic testing of hereditary spastic paraplegia

Orvosi Hetilap ◽

10.1556/oh.2015.30014 ◽

2015 ◽

Vol 156 (3) ◽

pp. 113-117 ◽

Cited By ~ 1

Author(s):

Kinga Hadzsiev ◽

László Balikó ◽

Katalin Komlósi ◽

Anett Lőcsei-Fekete ◽

Györgyi Csábi ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Molecular Testing ◽

Spastic Paraplegia ◽

Chain Reaction ◽

Hereditary Spastic Paraplegias ◽

Gene Testing ◽

New Information ◽

Common Causes ◽

Polymerase Chain ◽

Dependent Probe

Introduction: Hereditary spastic paraplegia is the overall term for clinically and genetically diverse disorders characterized with progressive and variable severe lower extremity spasticity. The most common causes of autosomal dominantly inherited hereditary spastic paraplegias are different mutations of the spastin gene with variable incidence in different ethnic groups, ranging between 15–40%. Mutations in the spastin gene lead to loss of spastins function, causing progressive neuronal failure, which results in axon degeneration finally. Aim: The molecular testing of spastin gene is available in the institution of the authors since January, 2014. The experience gained with the examination of the first eleven patients is described in this article. Method: After polymerase chain reaction, Sanger sequencing was performed to examine the 17 exons of the spastin gene. Multiplex ligation-dependent probe amplification was performed to detect greater rearrangements in the spastin gene. Eight of the patients were examined in the genetic counseling clinic of the authors and after detailed phenotype assessment spastin gene testing was obtained. The other three patients were referred to the laboratory from different outpatient clinics. Results: Out of the 11 examined patients, four different pathogenic mutations were found in 5 patients. Conclusions: The first Hungarian data, gained with the examination of spastin gene are presented in this article. The five patients, in whom mutations were detected, represent 45.5% of all tested patients with hereditary spastic paraplegia, which is similar to those published in the international literature. Molecular testing and subsequent detailed genotype-phenotype correlations of the Hungarian patients may serve valuable new information about the disease, which later on may influence our therapeutic possibilities and decisions. Orv. Hetil., 2015, 156(3), 113–117.

Download Full-text

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples

Genes ◽

10.3390/genes12070962 ◽

2021 ◽

Vol 12 (7) ◽

pp. 962

Author(s):

Francesca Peluso ◽

Stefano Giuseppe Caraffi ◽

Roberta Zuntini ◽

Gabriele Trimarchi ◽

Ivan Ivanovski ◽

...

Keyword(s):

Exome Sequencing ◽

Heart Defects ◽

Complex Phenotype ◽

Splicing Variant ◽

Whole Exome ◽

Brain Malformations ◽

The Right ◽

Gene Panels ◽

Second Toe

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.

Download Full-text

Application of a Clinical Workflow May Lead to Increased Diagnostic Precision in Hereditary Spastic Paraplegias and Cerebellar Ataxias: A Single Center Experience

Brain Sciences ◽

10.3390/brainsci11020246 ◽

2021 ◽

Vol 11 (2) ◽

pp. 246 ◽

Cited By ~ 1

Author(s):

Vittorio Riso ◽

Salvatore Rossi ◽

Tommaso Nicoletti ◽

Alessandra Tessa ◽

Lorena Travaglini ◽

...

Keyword(s):

Diagnostic Yield ◽

Genetic Diagnosis ◽

Molecular Diagnostic ◽

Molecular Heterogeneity ◽

Spinocerebellar Ataxias ◽

Next Generation ◽

Clinical Workflow ◽

Hereditary Spastic Paraplegias ◽

Cerebellar Ataxias ◽

Gene Panels

The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients’ selection. To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels. Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era.

Download Full-text

Diagnostic Utility of Whole Exome Sequencing in the Neuromuscular Clinic

Neuropediatrics ◽

10.1055/s-0039-1677734 ◽

2019 ◽

Vol 50 (02) ◽

pp. 096-102 ◽

Cited By ~ 5

Author(s):

Matthew Pastore ◽

Rachel Schrader ◽

Emily Sites ◽

Dennis Bartholomew ◽

Chang-Yong Tsao ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Gene ◽

Genetic Diagnosis ◽

Childhood Onset ◽

Diagnostic Odyssey ◽

Whole Exome ◽

Gene Panels ◽

The Impact ◽

Generation Sequencing

AbstractNext-generation sequencing is a powerful diagnostic tool, yet it has proven inadequate to establish a diagnosis in all cases of congenital hypotonia or childhood onset weakness. We sought to describe the impact of whole exome sequencing (WES), which has only recently become widely available clinically, on molecular diagnosis in the Nationwide Children's Hospital Neuromuscular clinics. We reviewed records of all patients in our clinic with pediatric onset of symptoms who had WES done since 2013. Patients were included if clinical suspicion was high for a neuromuscular disease. Clinical WES was performed in 30 families, representing 31 patients, all of whom were seen for hypotonia, weakness, or gait disturbance. Probands had between 2 and 12 genetic diagnostic tests prior to obtaining WES. A genetic diagnosis was established in 11 families (37%), and in 12 patients (39%), with mutations in 10 different genes. Five of these genes have only been associated with disease since 2013, and were not previously represented on clinically available disease gene panels. Our results confirm the utility of WES in the clinical setting, particularly for genetically heterogeneous syndromes. The availability of WES can provide an end to the diagnostic odyssey for parents and allow for expansion of phenotypes.

Download Full-text

Evaluation of Diagnostic Strategies for Fetal Skeletal Dysplasia Using Ultrasound Scan and Gene Testing: A Preliminary Study in Wu Han, China

10.21203/rs.3.rs-1089413/v1 ◽

2021 ◽

Author(s):

Wanlu Liu ◽

Jing Cao ◽

Xinwei Shi ◽

Yuqi Li ◽

Fuyuan Qiao ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Skeletal Dysplasia ◽

Genetic Diagnosis ◽

Gene Variants ◽

Sonographic Examination ◽

Gene Testing ◽

Whole Exome ◽

Preliminary Study ◽

One Year

Abstract Objective: The aim of this study was to deliver prenatal diagnosis through sonographic examination and gene variation testing, and to evaluate the outcome of applied strategies in prenatal diagnosisMethods: From September 2015 to April 2021, the study investigated 24 cases with suspected short long bones, which were obtained from the prenatal diagnosis center of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. The likely pathogenic gene variants were analyzed by multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) and further determined with the accuracy of the prenatal diagnosis for fetal skeletal dysplasia through one year follow-up survey. Results: ① We found fetal skeletal dysplasia or malformation in 8 cases (account for 33.3%) before 24 weeks of gestation and in the rest cases after 30 weeks of gestation. ② Out of 24 cases, likely pathogenic gene variants in FGFR3, FBN2, COL1A2, CUL7 and DYNC2H1 were detected for 6 cases; genetic variants in FGFR3, IMPAD1 and GORAB as possibly lethal mutations were identified in other 6 cases; and gene variants in WNT1, FBN1, OBSL1, COL1A1, DYNC2H1 and NEK1, known as Variant of Undetermined Significance (VUS), were found in 4 cases. The rest 8 cases showed undetectable mutation in the whole exome sequencing (WES) analysis.③ A genetic diagnosis determined 12 different skeletal dysplasia genotypes in 14/24 (58.3%) cases. The other 10 cases with wild type gene (41.7%) were normal and well developed in one-year follow-up survey after study.Conclusion: Features of fatal skeletal dysplasia can be identified in utero using fetal ultrasound and gene testing. Sonographic examination combining with genetic diagnosis showed advance in prenatal diagnosis in the preliminary study and the applied strategy could be used to help with improving the accuracy of prenatal diagnosis for fetal skeletal dysplasia.

Download Full-text

Exome Sequencing Identifies a Mutation (Y740C) in Spastic Paraplegia 7 Gene Associated with Adult-Onset Primary Lateral Sclerosis in a Chinese Family

European Neurology ◽

10.1159/000500672 ◽

2019 ◽

Vol 81 (1-2) ◽

pp. 87-93 ◽

Cited By ~ 1

Author(s):

Yihui Liu ◽

Jiang Xu ◽

Wanyun Tao ◽

Changbiao Fu ◽

Jiangbing Liu ◽

...

Keyword(s):

Motor Neuron ◽

Exome Sequencing ◽

Genetic Diagnosis ◽

Chinese Family ◽

Primary Lateral Sclerosis ◽

Adult Onset ◽

Spastic Paraplegia ◽

Limb Weakness ◽

Primary Lateral ◽

Lateral Sclerosis

Background: Primary lateral sclerosis (PLS) is considered a rare variant of motor neuron disease (MND) characterized by selective upper motor neuron dysfunction leading to limb weakness, spasticity, and even bulbar symptoms. Previous studies have demonstrated that mutations in ALSIN, spastic paraplegia 7 (SPG7), TBK1, ALS2, ERLIN2, and FIG4 are responsible for PLS. Most of them occurred in childhood to young-adult onset patients. The aim of this study was to identify the genetic lesion of patients with adult-onset PLS. Methods: We applied whole-exome sequencing (WES) and MND and ataxia-related genes filtering strategies to discover the genetic factors in a Chinese adult-onset PLS family. Sanger sequencing was used in the cosegregation analysis in the affected family members. Results: A mutation (c.2219A>G/p.Y740C) in exon 17 of SPG7 was identified in an adult-onset PLS patient and cosegregated with the affected members in this family. Meanwhile, the mutation was predicted to be deleterious by 3 bioinformatics programs (Polymorphism phenotyping-2, sorting intolerant from tolerant and MutationTaster). This variant may cause the structure changes of paraplegin protein. Conclusions: We employed WES to detect a missense mutation of SPG7 gene in a PLS family. This finding expands the spectrum of known SPG7 mutations, and it may contribute to novel approaches to genetic diagnosis and counseling of families with PLS.

Download Full-text

The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

Genes ◽

10.3390/genes12111824 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1824

Author(s):

Cristina Villanueva-Mendoza ◽

Miquel Tuson ◽

David Apam-Garduño ◽

Marta de Castro-Miró ◽

Raul Tonda ◽

...

Keyword(s):

Diagnostic Yield ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Whole Exome ◽

Genetic Landscape ◽

Genetic Features ◽

Gene Panels

In this work, we aimed to provide the genetic diagnosis of a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico. Our data add valuable information to the genetic portrait in rare ocular diseases of Mesoamerican populations, which are mostly under-represented in genetic studies. A cohort of 144 unrelated probands with a clinical diagnosis of IRD were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences). Four unsolved cases were analyzed by whole-exome sequencing (WES). The pathogenicity of new variants was assessed by in silico prediction algorithms and classified following the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic or likely pathogenic variants were identified in 105 probands, with a final diagnostic yield of 72.9%; 17 cases (11.8%) were partially solved. Eighteen patients were clinically reclassified after a genetic diagnostic test (17.1%). In our Mexican cohort, mutations in 48 genes were found, with ABCA4, CRB1, RPGR and USH2A as the major contributors. Notably, over 50 new putatively pathogenic variants were identified. Our data highlight cases with relevant clinical and genetic features due to mutations in the RAB28 and CWC27 genes, enrich the novel mutation repertoire and expand the IRD landscape of the Mexican population.

Download Full-text

Translation and validation into Brazilian Portuguese of the Spastic Paraplegia Rating Scale (SPRS)

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20160047 ◽

2016 ◽

Vol 74 (6) ◽

pp. 489-494 ◽

Cited By ~ 4

Author(s):

Katiane R. Servelhere ◽

Ingrid Faber ◽

Ana Carolina Coan ◽

Marcondes França Junior

Keyword(s):

Disease Duration ◽

Rating Scale ◽

Correlation Coefficients ◽

Brazilian Portuguese ◽

Spastic Paraplegia ◽

Limb Weakness ◽

Hereditary Spastic Paraplegias ◽

Coefficients Of Variation ◽

Clinical Instrument ◽

Translation And Validation

ABSTRACT Hereditary spastic paraplegias (HSP) are characterized by progressive lower limb weakness and spasticity. There are no validated instruments to quantify disease severity in Portuguese. Objective To translate and validate the Spastic Paraplegia Rating Scale (SPRS) into Brazilian-Portuguese. Method Two experienced and English-fluent neurologists translated SPRS into Portuguese, creating SPRS-BR. We then assessed inter and intra-rater reliability of this version using coefficients of correlation and variability in a cohort of 30 patients. Results Mean age of patients and disease duration were 47.7 ± 10.5 and 17.0 ± 10.6 years, respectively. Twenty-one had pure HSP and SPG4 was the most frequent genotype. Mean Rankin and SPRS-BR scores were 2.2 ± 0.9 and 19.9 ± 9.9, respectively. Mean intra and inter-rater correlation coefficients of SPRS-BR scores were 0.951 and 0.934, whereas coefficients of variation were 11.5% (inter-rater) and 9.9% (intra-rater). Cronbach’s alpha for the whole SPRS-BR scale was 0.873. Conclusion SPRS-BR is a useful, reliable and valid clinical instrument.

Download Full-text