De novo variant in KIF26B is associated with pontocerebellar hypoplasia with infantile spinal muscular atrophy

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1. We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

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Genomic analysis of a spinal muscular atrophy (SMA) discordant family identifies a novel mutation in TLL2, an activator of growth differentiation factor 8 (myostatin): a case report

BMC Medical Genetics ◽

10.1186/s12881-019-0935-3 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Jianping Jiang ◽

Jinwei Huang ◽

Jianlei Gu ◽

Xiaoshu Cai ◽

Hongyu Zhao ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

De Novo ◽

Muscular Atrophy ◽

Novel Mutation ◽

Genomic Analysis ◽

Neuromuscular Disorder ◽

De Novo Mutation ◽

Compound Heterozygous ◽

Mice Model ◽

Compound Heterozygous Mutations

Abstract Background Spinal muscular atrophy (SMA) is a rare neuromuscular disorder threating hundreds of thousands of lives worldwide. And the severity of SMA differs among different clinical types, which has been demonstrated to be modified by factors like SMN2, SERF1, NAIP, GTF2H2 and PLS3. However, the severities of many SMA cases, especially the cases within a family, often failed to be explained by these modifiers. Therefore, other modifiers are still waiting to be explored. Case presentation In this study, we presented a rare case of SMA discordant family with a mild SMA male patient and a severe SMA female patient. The two SMA cases fulfilled the diagnostic criteria defined by the International SMA Consortium. With whole exome sequencing, we confirmed the heterozygous deletion of exon7 at SMN1 on the parents’ genomes and the homozygous deletions on the two patients’ genomes. The MLPA results confirmed the deletions and indicated that all the family members carry two copies of SMN2, SERF1, NAIP and GTF2H2. Further genomic analysis identified compound heterozygous mutations at TLL2 on the male patient’s genome, and compound heterozygous mutations at VPS13A and the de novo mutation at AGAP5 on female patient’s genome. TLL2 is an activator of myostatin, which negatively regulates the growth of skeletal muscle tissue. Mutation in TLL2 has been proved to increase muscular function in mice model. VPS13A encodes proteins that control the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. And AGAP5 was reported to have GTPase activator activity. Conclusions We reported a case of SMA discordant family and identified mutations at TLL2, VPS13A and AGAP5 on the patients’ genomes. The mutations at TLL2 were predicted to be pathogenic and are likely to alleviate the severity of the male SMA patient. Our finding broadens the spectrum of genetic modifiers of SMA and will contribute to accurate counseling of SMA affected patients and families.

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RESTORE: A Prospective Multinational Registry of Patients with Genetically Confirmed Spinal Muscular Atrophy - Rationale and Study Design

Journal of Neuromuscular Diseases ◽

10.3233/jnd-190451 ◽

2020 ◽

Vol 7 (2) ◽

pp. 145-152 ◽

Cited By ~ 1

Author(s):

Richard S. Finkel ◽

John W. Day ◽

Darryl C. De Vivo ◽

Janbernd Kirschner ◽

Eugenio Mercuri ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

De Novo ◽

Muscular Atrophy ◽

Work Productivity ◽

Healthcare Resource Utilization ◽

Real World Data ◽

Activity Impairment ◽

Survival Status ◽

Usual Clinical Practice

Background: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to document their impact on patients and caregivers. Objectives: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments. Design and Methods: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- Hôpitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival. Status: Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites. Conclusions: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes.

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The Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Gene VRK1 Regulates Neuronal Migration through an Amyloid- Precursor Protein-Dependent Mechanism

Journal of Neuroscience ◽

10.1523/jneurosci.1998-14.2015 ◽

2015 ◽

Vol 35 (3) ◽

pp. 936-942 ◽

Cited By ~ 22

Author(s):

H. Vinograd-Byk ◽

T. Sapir ◽

L. Cantarero ◽

P. A. Lazo ◽

S. Zeligson ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Spinal Muscular Atrophy ◽

Neuronal Migration ◽

Muscular Atrophy ◽

Precursor Protein ◽

Pontocerebellar Hypoplasia ◽

Dependent Mechanism

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X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C>T substitution in the UBA1 gene

Neuromuscular Disorders ◽

10.1016/j.nmd.2015.05.001 ◽

2015 ◽

Vol 25 (8) ◽

pp. 661-666 ◽

Cited By ~ 5

Author(s):

Maria Jędrzejowska ◽

Elżbieta Jakubowska-Pietkiewicz ◽

Anna Kostera-Pruszczyk

Keyword(s):

Spinal Muscular Atrophy ◽

De Novo ◽

Muscular Atrophy

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Exome Sequencing Identifies De Novo DYNC1H1 Mutations Associated With Distal Spinal Muscular Atrophy and Malformations of Cortical Development

Journal of Child Neurology ◽

10.1177/0883073816683083 ◽

2016 ◽

Vol 32 (4) ◽

pp. 379-386 ◽

Cited By ~ 2

Author(s):

Yulin Chen ◽

Yufei Xu ◽

Guoqiang Li ◽

Niu Li ◽

Tingting Yu ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Exome Sequencing ◽

Missense Mutation ◽

De Novo ◽

Muscular Atrophy ◽

Cortical Development ◽

Retrograde Transport ◽

Cytoplasmic Dynein ◽

Malformations Of Cortical Development ◽

Heterozygous Missense Mutation

Exome sequencing has become a formidable tool for identifying potential de novo variants in causative genes of human diseases, such as neurodegenerative disorders. This article describes a 16-month-old girl with spinal muscular atrophy with lower extremity predominance and a 13-month-old girl with malformations of cortical development. Exome sequencing identified a novel de novo heterozygous missense mutation c.3395G>A (p.Gly1132Glu) and a previously reported de novo heterozygous missense mutation c.10151G>A (p.Arg3384Gln) in the DYNC1H1 gene. Bioinformatics predictions for c.3395G>A and c.10151G>A indicated pathogenicity of the mutations. DYNC1H1 is a pivotal component of cytoplasmic dynein complex, which is a microtubule-related motor involved in retrograde transport. Previous studies indicated that mutant dynein showed decreased run-length of the motor proteins and diminished retrograde transport, which were clearly associated with neuronal death and neurologic diseases. The present findings expand the mutational spectrum of the DYNC1H1 gene, reemphasizing the significance of the DYNC1H1 protein in the functioning of neurons.

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