Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in<i>ATL1</i>Blurs Autosomal Dominant Inheritance of Spastic Paraplegia

Varga, Rita E.; Schüle, Rebecca; Fadel, H.; Valenzuela, Irene; Speziani, Fiorella; Gonzalez, Michael; Руденская, Г. Е.; Nürnberg, Gudrun; Thiele, Holger; Altmüller, Janine; Álvarez, Victoria; Gamez, Josep; Garbern, James; Nürnberg, Peter; Züchner, Stephan; Beetz, Christian

doi:10.1002/humu.22309

Cited by 22 publications

(16 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic studies show that B20% of cases reported with HSP are negative for mutations, and one potential explanation could be misinterpretation of the inheritance pattern when selecting candidate genes. 15 Our data demonstrate that ATL1 mutations can be taken into account in families with nondominant and even recessive inheritance of HSP. WES or complete gene panels in order to target all known SPG loci are thus preferred methods for improved genetic diagnosis in HSP that circumvents a selection bias based on inheritance patterns.…”

Section: Discussionmentioning

confidence: 55%

“…15 The identification of ATL1 mutation in autosomal dominant HSN1D 21 further illustrates the clinical variability associated with ATL1 mutations. 22 The family investigated herein segregates 'pure' HSP compatible with both autosomal recessive and dominant inheritance and, strikingly, only males are affected.…”

Section: Discussionmentioning

confidence: 93%

“…9,[11][12][13][14] A further complicating factor in SPG3A is a gender-dependent penetrance with a preponderance for males in some families. 15 We identified a large family segregating an uncomplicated and early onset form of HSP. Exome sequencing revealed homozygosity for a novel ATL1 missense variant in the six affected family members, whereas heterozygous carriers are asymptomatic.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

et al. 2014

View full text Add to dashboard Cite

Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for B80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G4A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

et al. 2014

View full text Add to dashboard Cite

show abstract

“…It is possible that the amyotrophy of the extremities and retinitis pigmentosa were observed because ATL1 mutations could affect pathways other than the corticospinal tract, and the variability of clinical presentation with the same mutation may be due to genetic or environmental modulation. Moreover, incomplete penetrant was observed in a family with the c. 1246C>T, which was only reported in 3 European SPG3A cases with the mutations c.1243C>T and c.1244G>A [40,41]. Mutations in the C-terminal cytoplasmic part of the protein may be less deleterious, accounting for its incomplete penetrance, or varying penetrance may be due to environmental and/or genetic factors.…”

Section: Discussionmentioning

confidence: 99%

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Luo¹,

Chen²,

Zhan³

et al. 2014

Neurodegener Dis

View full text Add to dashboard Cite

Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.

show abstract

“…Complicated SPG3A and the late-onset form are very rare (Sauter et al, 2004;Ivanova et al, 2007). AD inheritance is common, although autosomal recessive inheritance and sex-related penetrance have also been reported (Varga et al, 2013;Khan et al, 2014). In this study, family 4, which segregates the c.1204T>G ATL1 mutation, presents infancy-onset HSP, and the lower limb spasticity of female patients in this family is too severe to permit walking without double crutches.…”

Section: Discussionmentioning

confidence: 66%

Mutation analysis of four Chinese families with pure hereditary spastic paraplegia: pseudo- X-linked dominant inheritance and male lethality due to a novel ATL1 mutation

Zhao

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. We studied four Chinese families with pure hereditary spastic paraplegia (HSP) to investigate the clinical features and associated genetic mutations. Linkage analysis was performed for all families to map the disease locus onto autosomal chromosomes, and related loci involved in HSP on the X chromosome were also examined. Polymerase chain reaction (PCR) sequencing was used to detect gene mutations. To confirm the influence of a splice-site mutation on mRNA, we used reverse transcription-PCR and direct sequencing. Linkage analysis and ATL1 gene sequencing of amniocytes were performed for prenatal genetic diagnosis. One missense variant (c.1517T>A) and a splice-site mutation (c.1245+1G>A) in SPAST, and two missense variants (c.715C>T, c.1204T>G) in ATL1 were identified. The c.1245+1G>A mutation caused a deletion of exon 9 in the SPAST gene. Prenatal genetic diagnosis showed that fetus did not carry the ALT1 c.1204T>G mutation. Follow-up was maintained for 5 years, and the negative result was confirmed by evidence of a healthy growing boy. We identified two novel mutations and two previously reported mutations in SPAST and ATL1, respectively. The family with the ATL1 c.1204T>G mutation exhibited male-lethality, female infancy-onset, and pseudo-X-linked dominant transmission, which had never been previously reported for HSP. Characteristic facial features were also noticed. The boy on whom prenatal gene diagnosis was performed is healthy and without unusual facies, suggesting that the c.1204T>G mutation might be related to these features. The results extend the genetic spectrum of HSP and suggest that linkage analysis remains a powerful tool in gene discovery studies.

show abstract

Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot inATL1Blurs Autosomal Dominant Inheritance of Spastic Paraplegia

Cited by 22 publications

References 17 publications

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

Mutation and Clinical Characteristics of Autosomal-Dominant Hereditary Spastic Paraplegias in China

Mutation analysis of four Chinese families with pure hereditary spastic paraplegia: pseudo- X-linked dominant inheritance and male lethality due to a novel ATL1 mutation

Contact Info

Product

Resources

About