Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

Tazelaar, Gijs H.P.; Dekker, Annelot M.; Vugt, Joke J.F.A. van; Spek, Rick A. van der; Westeneng, Henk‐Jan; Kool, Lindy; Kenna, Kevin P.; Rheenen, Wouter van; Pulit, Sara L.; McLaughlin, Russell L.; Sproviero, William; Iacoangeli, Alfredo; Hübers, Annemarie; Brenner, Dávid; Morrison, Karen; Shaw, Pamela J.; Shaw, Christopher E.; Panades, Mónica Povedano; Pardina, Jesús S. Mora; Glass, Jonathan D.; Hardiman, Orla; Al‐Chalabi, Ammar; Damme, Philip Van; Robberecht, Wim; Landers, John E.; Ludolph, Albert C.; Weishaupt, Jochen H.; Berg, Leonard H van den; Veldink, Jan H.; Es, Michael A. van

doi:10.1016/j.neurobiolaging.2018.09.012

Cited by 30 publications

(27 citation statements)

References 22 publications

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“…In controls and in the remaining ALS cases, repeat length was variable ranging from 5 to 13. Similar to previous findings [38,40], the most frequent alleles consisted of either 7 or 8 repeats, with respective allele frequencies being 26.1% and 67.4% in ALS patients, and 7.7% and 73.1% in controls.…”

Section: Repeat Expansions In C9orf72 Atxn2 and Nipa1 Genessupporting

confidence: 90%

Genetic analysis of ALS cases in the isolated island population of Malta

et al. 2021

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Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified throughout a 2-year window. Cases were largely male (66.7%) with a predominant spinal onset of symptoms (70.8%). Disease onset occurred around mid-age (median age: 64 years, men; 59.5 years, female); 12.5% had familial ALS (fALS). Annual incidence rate was 2.48 (95% CI 1.59–3.68) per 100,000 person-years. Male-to-female incidence ratio was 1.93:1. Prevalence was 3.44 (95% CI 2.01–5.52) cases per 100,000 inhabitants on 31st December 2018. Whole-genome sequencing allowed us to determine rare DNA variants that change the protein-coding sequence of ALS-associated genes. Interestingly, the Maltese ALS patient cohort was found to be negative for deleterious variants in C9orf72, SOD1, TARDBP or FUS genes, which are the most commonly mutated ALS genes globally. Nonetheless, ALS-associated repeat expansions were identified in ATXN2 and NIPA1. Variants predicted to be damaging were also detected in ALS2, DAO, DCTN1, ERBB4, SETX, SCFD1 and SPG11. A total of 40% of patients with sporadic ALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene, whilst the genetic cause of two thirds of fALS cases could not be pinpointed to known ALS genes or risk loci. This warrants further studies to elucidate novel genes that cause ALS in this unique population isolate.

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Section: Repeat Expansions In C9orf72 Atxn2 and Nipa1 Genessupporting

confidence: 90%

Genetic analysis of ALS cases in the isolated island population of Malta

et al. 2021

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“…Of the genes in this region, certain pathogenic variants in the NIPA1 gene causes an autosomal dominant form of spastic paraplegia and triplet repeat expansion within this gene is associated with a higher risk for amyotrophic lateral sclerosis [6,7]. Haploinsufficiency of this gene has not been reported to cause these conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Deletions can range from approximately 320 kb to 500 kb, though all four genes within this 320-kb region are highly conserved and, when disturbed, are associated with or cause neurological, motor, intellectual, and behavioral problems. For example, specific missense variants of the NIPA1 (non-imprinted in PWS/AS 1; OMIM # 608145) gene are known to cause autosomal dominant hereditary spastic paraplegia and postural disturbance; repeat expansions have recently been associated with amyotrophic lateral sclerosis [6,7]. The NIPA1 protein is known to mediate magnesium transport and is highly expressed in the brain [8,9].…”

Section: Introductionmentioning

confidence: 99%

Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome

Serrano

Loddo

et al. 2019

IJMS

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To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER database, and the primary literature. Chi-squared and Mann-Whitney U tests were used to test for differences in specific and grouped clinical symptoms based on parental inheritance and proband gender. Analyses controlled for sibling sets and individuals with additional variants of uncertain significance (VOUS). Among all probands, maternal deletions were associated with macrocephaly (p = 0.016) and autism spectrum disorder (ASD; p = 0.02), while paternal deletions were associated with congenital heart disease (CHD; p = 0.004). Excluding sibling sets, maternal deletions were associated with epilepsy as well as macrocephaly (p < 0.05), while paternal deletions were associated with CHD and abnormal muscular phenotypes (p < 0.05). Excluding sibling sets and probands with an additional VOUS, maternal deletions were associated with epilepsy (p = 0.019) and paternal deletions associated with muscular phenotypes (p = 0.008). Significant gender-based differences were also observed. Our results supported POEs of this deletion and included macrocephaly, epilepsy and ASD in maternal deletions with CHD and abnormal muscular phenotypes seen in paternal deletions.

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“…Over the last 15 years studies (genomewide association studies and others) have identified genetic risk factors for SALS at almost an exponential pace. We now know that polymorphisms and repeat expansions in genes like unc13a, NEK1, KIF5a, ATXN2 and NIPA1 are associated with ALS [62][63][64][65]. Interestingly, as studies in SALS are getting larger and therefore have the statistical power to analyze genetic variants with lower frequencies, overlap between FALS and SALS is emerging.…”

Section: Geneticsmentioning

confidence: 99%

Is it accurate to classify ALS as a neuromuscular disorder?

Goedee

Westeneng

et al. 2020

Expert Review of Neurotherapeutics

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Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder. Areas covered: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies. Expert opinion: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.

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Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort

Cited by 30 publications

References 22 publications

Genetic analysis of ALS cases in the isolated island population of Malta

Genetic analysis of ALS cases in the isolated island population of Malta

Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome

Is it accurate to classify ALS as a neuromuscular disorder?

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