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Evidence for Autosomal Recessive Inheritance in SPG3A Caused by Homozygosity for a Novel ATL1 Missense Mutation

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Evidence for Autosomal Recessive Inheritance in SPG3A Caused by Homozygosity for a Novel ATL1 Missense Mutation European Journal of Human Genetics (2014) 22, 1180–1184 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation Tahir Naeem Khan1, Joakim Klar2, Muhammad Tariq1, Shehla Anjum Baig3, Naveed Altaf Malik1, Raja Yousaf4, Shahid Mahmood Baig1 and Niklas Dahl*,2 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. European Journal of Human Genetics (2014) 22, 1180–1184; doi:10.1038/ejhg.2014.5; published online 29 January 2014 Keywords: SPG3A; autosomal recessive; ATL1 gene INTRODUCTION We identified a large family segregating an uncomplicated and Hereditary spastic paraplegias (HSPs) or spastic paraplegias (SPGs) early onset form of HSP. Exome sequencing revealed homozygosity belong to a clinically and genetically heterogeneous group of disorders for a novel ATL1 missense variant in the six affected family members, caused by upper motor neuron degeneration.1 To date, more than 55 whereas heterozygous carriers are asymptomatic. We therefore different gene loci have been mapped for HSP (SPG1-SPG56) consider autosomal recessive SPG3A as a novel albeit rare genetic including autosomal dominant, autosomal recessive and the more form of unexplained HSP. rare X-linked forms.2 The dominant cases are predominantly ‘pure’ forms with symptoms mainly restricted to the lower extremities. Heterozygous mutations in the SPAST gene cause SPG4 and account MATERIALS AND METHODS for 40% of all autosomal dominant cases followed by mutations in the Patients ATL1 gene in SPG3A in B10% of cases.2–4 Autosomal recessive forms A consanguineous Pakistani family segregates pure HSP in six males in two generations. Owing to consanguinity, both autosomal dominant and recessive of HSP comprise mainly ‘complicated’ clinical types with extensive inheritance seemed possible (Figure 1a). The clinical onset was before 2 years 5–7 neurological and non-neurological manifestations. The majority of of age (y.o.a.) with spastic gait and toe walking. Symptoms progressed slowly HSP genes are associated with very rare or even unique clinical forms. with bilateral spasticity of the lower limbs, brisk reflexes, reduced vibration Thus, yet unknown genetic mechanisms are a conceivable explanation sensation, peripheral numbness and tinglings, urinary bladder hyperactivity, for why directed gene analysis fails to identify mutations in B20% of scoliosis and pes cavus (Table 1). Cognitive functions were normal and the cases.8 Another plausible explanation for the ‘missed heritability’ in upper limbs were unaffected. Individuals III:1 and III:5 acquired walking HSP is uncertainty about inheritance patterns as illustrated here in assistance before attaining the age of 10 years. The affected members were SPG3A, a ‘pure’ form of SPG usually apparent before the age of 10 between 3 and 45 years of age upon investigation (Table 1). Two affected brothers (III:3 and III:5) and their healthy sister (III:6) were available for brain years.9,10 In SPG3A, diagnosis may be complicated owing to late onset 9 and spinal cord magnetic resonance imaging (MRI), nerve conduction studies and, in particular, to reduced penetrance that may be as low as 30% (NCS) and electromyography (EMG). The NCS and EMG assessments were 9,11–14 for specific ATL1 mutations. A further complicating factor in normal and without signs of neuropathy or myopathy in the three individuals. SPG3A is a gender-dependent penetrance with a preponderance for The MRI revealed mild foraminal stenosis at the cervical level in the affected males in some families.15 individuals III:3 and III:5 interpreted as secondary to scoliosis. No MRI 1Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan; 2Department of Immunology, Genetics and Pathology, Science for Life Laboratory at Uppsala University, Biomedical Center, Uppsala, Sweden; 3Department of Pathology, Children’s Hospital, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan; 4Department of Neurology, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan *Correspondence: Professor N Dahl, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Center, Box 815, Uppsala 751 08, Sweden. Tel: +46 18 6112799; Fax: +46 18 554025; E-mail: [email protected] Received 8 August 2013; revised 11 December 2013; accepted 18 December 2013; published online 29 January 2014 Evidence for autosomal recessive inheritance in SPG3A TN Khan et al 1181 Figure 1 Pedigree of the family segregating HSP and analysis of the ATL1 mutation. (a) The consanguineous family consists of two loops with two first- cousin marriages and six male individuals affected by pure HSP (filled symbols). The genotype at cDNA position 353 of ATL1 is shown below each symbol. Affected individuals are homozygous for the c.353G4A p.(Arg118Gln) mutation, whereas seven heterozygous family members are asymptomatic. The two females II:1 and II:4 are distantly related, but the precise relationship was unclear. (b) Sequence chromatogram showing part of ATL1 exon 4 (NM_001127713.1) obtained from a healthy control (top), individual III:6 (middle) and the affected individual III:1 (bottom). The ATL1 mutation c.353G4A p.(Arg118Gln) is indicated by an arrow. The asterisk denotes a synonymous SNP (rs1060197) with allele frequencies 0.19/0.81 (dbSNP) and without predicted effects. (c) Relative position of the p.(Arg118Gln) substitution in the GTPase domain of the atlastin-1 protein (top) and degree of conservation of the Arg118 residue (shaded) across different species. N, N-terminus; M, middle domain; TM, transmembrane domains. European Journal of Human Genetics Evidence for autosomal recessive inheritance in SPG3A TN Khan et al 1182 Table 1 Clinical features of the family segregating an ATL1 mutation and autosomal recessive SPG3A Individual II:1 II:3 II:4 III:1 III:2 III:3 III:4 III:5 III:6 IV:1 IV:2 IV:3 IV:4 Genotype wt/m wt/m wt/m m/m wt/m m/m wt/m m/m wt/m m/m m/m wt/m m/m Age (years) 66 75 70 45 35 31 32 43 32 12 10 7 3 Sex F M F M F M F M F M M M M Age at disease onset (years) ÀÀÀ 1 À 1 À 1 À 11À 1 Spastic gait ÀÀÀþÀþ Àþ À þ þ Àþ Difficulty in walking ÀÀÀþÀþ Àþ À þ þ Àþ LL spasticity ÀÀÀþÀþ Àþ À þ þ Àþ UL spasticity ÀÀÀÀÀÀÀÀ À À ÀÀÀ Scoliosis ÀÀÀþÀþ Àþ À À ÀÀÀ Hyperactive urinary bladder ÀÀÀþÀþ Àþ À À ÀÀÀ Pes cavus ÀÀÀþÀþ Àþ À þ þ Àþ Babinski reflex þÀþ þ À þ À þ À þ þ Àþ Clonus ÀÀÀþÀþ Àþ À þ þ Àþ Radicular pain ÀÀÀÀÀÀÀÀ À þ ÀÀÀ Excessive tingling ÀÀÀþÀþ Àþ À þ þ Àþ Numbness ÀÀÀþÀþ Àþ À þ þ Àþ Muscle tone Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Cognitive dysfunction ÀÀÀÀÀÀÀÀ À À ÀÀÀ Walking assistance ÀÀÀþÀÀÀþ À À ÀÀÀ Vibration sensation (peripheral) Normal Normal Normal Decreased Normal Decreased Normal Decreased Decreased Decreased Decreased NI NI Peripheral sensation Normal Normal Normal Decreased Normal Decreased Normal Normal Normal Decreased Decreased NI NI Pain perception (peripheral) Normal Normal Normal Normal Normal Decreased Normal Normal Normal Normal Normal NI NI Reflexes of lower extremities Normal Normal Normal Hyper- Normal Hyper- Normal Hyper- Normal Hyper- Hyper- NI NI reflexia reflexia reflexia reflexia reflexia Paresthesia ÀÀÀþÀÀÀÀ À þ þNI NI EMG findings NI NI NI NI NI Normal NI Normal Normal NI NI NI NI NCS findings NI NI NI NI NI Normal NI Normal Normal NI NI NI NI Brain MRI NI NI NI NI NI Normal NI Normal Normal NI NI NI NI Cervical Foraminal Stenosis (MRI) NI NI NI NI NI þ NI þÀNI NI NI NI Abbreviations: þ , present; À, absent; EMG, electromyography; F, female; LL, lower limbs; m, mutant; M, male; MRI, magnetic resonance imaging; NCS, nerve conduction studies; NI, not investigated; UL, Upper limbs; wt, wild-type. abnormalities were found in the healthy individual III:6 (Table 1). Clinical obtained from ANNOVAR16 and dbSNP135. Custom R scripts were used to investigations of five healthy first-degree relatives (II:1, III:2, III:4, III:6 and identify potentially damaging variants shared between the two patients while IV:3) to affected individuals showed normal gait without deformities of the absent in any of the other B400 exomes in our in-house database. lower limbs (Table 1). The three family members in generation II were Bidirectional Sanger sequencing (Applied Biosystems BigDye Terminator v3.1 investigated at 66–75 y.o.a. and they had a normal neurological status. One Cycle Sequencing Kit, Applied Biosystems) on a 3730xl DNA Analyzer healthy female (ind. III:6) showed a slightly impaired distal vibration sensation (Applied Biosystems) was used for segregation analysis of the ATL1 and in lower limbs/malleoli at 36 y.o.a.
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