Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias.
Eur J Hum Genet. 2017-08-23; 25(11): 1217-1228
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1. Eur J Hum Genet. 2017 Nov;25(11):1217-1228. doi: 10.1038/ejhg.2017.124. Epub 2017
Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to
be uncovered in hereditary spastic paraplegias.
Morais S(1)(2)(3)(4)(5)(6)(7)(8), Raymond L(4)(5)(6)(7)(8), Mairey
M(4)(5)(6)(7)(8), Coutinho P(1)(2), Brandão E(9), Ribeiro P(9), Loureiro
JL(1)(2)(9), Sequeiros J(1)(2)(3), Brice A(4)(5)(6)(7)(10), Alonso I(1)(2)(3),
(1)UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Universidade do
Porto, Porto, Portugal.
(2)Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto,
(3)Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do
Porto, Porto, Portugal.
(4)INSERM, U 1127, Paris, France.
(5)CNRS, UMR 7225, Paris, France.
(6)Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, Paris, France.
(7)Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
(8)Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris,
(9)Serviço de Neurologia, Centro Hospitalar de Entre o Douro e Vouga, Santa Maria
da Feira, Portugal.
(10)APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris,
Hereditary spastic paraplegias (HSP) are neurodegenerative disorders
characterized by lower limb spasticity and weakness that can be complicated by
other neurological or non-neurological signs. Despite a high genetic
heterogeneity (>60 causative genes), 40-70% of the families remain without a
molecular diagnosis. Analysis of one of the pioneer cohorts of 193 HSP families
generated in the early 1990s in Portugal highlighted that SPAST and SPG11 are the
most frequent diagnoses. We have now explored 98 unsolved families from this
series using custom next generation sequencing panels analyzing up to 70
candidate HSP genes. We identified the likely disease-causing variant in 20 of
the 98 families with KIF5A being the most frequently mutated gene. We also found
52 variants of unknown significance (VUS) in 38% of the cases. These new
diagnoses resulted in 42% of solved cases in the full Portuguese cohort (81/193).
Segregation of the variants was not always compatible with the presumed
inheritance, indicating that the analysis of all HSP genes regardless of the
inheritance mode can help to explain some cases. Our results show that there is
still a large set of unknown genes responsible for HSP and most likely novel
mechanisms or inheritance modes leading to the disease to be uncovered, but this
will require international collaborative efforts, particularly for the analysis
PMID: 28832565 [Indexed for MEDLINE]