30-40% genetic diagnosis gap in HSPs

Need to look elsewhere for full picture of HSP genetics


Despite huge advances in genetics knowledge and tools this century, and with most new findings identifying genes and variants of increasing rarity, there is a persistent 30 to 40% of all cases of HSP sent for genetic testing failing to yield a positive result. There is a need to look at non—traditional disease causation in HSP and employ emerging, sophisticated methods for analysing genetic data.

Read the full paper …


Stephan Züchner


Hereditary Spastic Paraplegia is an extraordinarily heterogeneous disease caused by over 50 Mendelian genes. Recent applications of next-generation sequencing, large scale data analysis, and data sharing/matchmaking, have discovered a quickly expanding set of additional HSP genes.


Since most recently discovered HSP genes are rare causes of the disease, there is a growing concern of a persisting diagnostic gap, estimated at 30-40%, and even higher for sporadic cases. This missing heritability may not be fully closed by classic Mendelian mutations in protein coding genes.


Here we show strategies and published examples of broadening areas of attention for Mendelian and non-Mendelian causes of HSP. We suggest a more inclusive perspective on the potential final architecture of HSP genomics. Efforts to narrow the heritability gap will ultimately lead to more precise and comprehensive genetic diagnoses, which is the starting point for emerging, highly specific gene therapies.


SOURCE: Front Neurol. 2018 Nov 26;9:958. doi: 10.3389/fneur.2018.00958. eCollection 2018. PMID: 30534106


Perspectives on the Genomics of HSP Beyond Mendelian Inheritance.


Bis-Brewer DM1,2Züchner S1,2.


1 Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States.

2 John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States.


Large HSP genetic screening study


Just 29% with positive genetic identification


This large and comprehensive HSP genetic screening study in Italy yielded just 29% positive diagnostic results, with 36% having mutations of unknown significance and the remaining 35% of cases unsolved. The study also identified a significant number of new mutations in very rare genes.



Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness.


Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity – there are over 80 potential disease-associated genes – and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming.


In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved.


This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.


SOURCE: Front Neurol. 2018 Dec 4;9:981. doi: 10.3389/fneur.2018.00981. eCollection 2018. PMID: 30564185


Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.


D’Amore A1,2, Tessa A1, Casali C3, Dotti MT4, Filla A5, Silvestri G6,7, Antenora A5, Astrea G1, Barghigiani M1, Battini R1, Battisti C4, Bruno I8, Cereda C9, Dato C10, Di Iorio G10, Donadio V11, Felicori M12, Fini N13, Fiorillo C14, Gallone S15, Gemignani F2, Gigli GL16, Graziano C17, Guerrini R18, Gurrieri F19, Kariminejad A20, Lieto M5, Marques LourenḈo C21, Malandrini A4, Mandich P22,23, Marcotulli C3, Mari F18, Massacesi L24, Melone MAB10, Mignarri A4, Milone R25, Musumeci O26, Pegoraro E27, Perna A6,7, Petrucci A28, Pini A12, Pochiero F29, Pons MR30, Ricca I1, Rossi S6,7, Seri M17, Stanzial F31, Tinelli F1, Toscano A26, Valente M16, Federico A4, Rubegni A1, Santorelli FM1.


1 Molecular Medicine, Pisa, Italy.

2 Department of Biology, University of Pisa, Pisa, Italy.

3 Department of Medical and Surgical Sciences and Biotechnologies, University of Rome Sapienza, Latina, Italy.

4 Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy.

5 Department of Neurosciences, Reproductive and Odontostomatologic Sciences, Federico II University, Naples, Italy.

6 IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.

7 Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.

8 Department of Pediatrics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.

9 Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy.

10 Second Division of Neurology, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Luigi Vanvitelli, Naples, Italy.

11 IRCCS Istituto delle Scienze Neurologiche di Bologna-UOC Clinica Neurologica, Bologna, Italy.

12 Istituto delle Scienze Neurologiche di Bologna-UOC Neuropsichiatria Infantile, Bologna, Italy.

13 Department of Neurosciences, Sant’Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.

14 Pediatric Neurology and Neuromuscular Disorders, University of Genoa and Istituto Giannina Gaslini, Genova, Italy.

15 Neurology I, Department of Neuroscience and Mental Health, AOU Città della Salute e della Scienza, Turin, Italy.

16 Neurology Clinic, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy.

17 Medical Genetics Unit, Sant’Orsola-Malpighi University Hospital, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

18 Pediatric Neurology Unit, Children’s Hospital A. Meyer, University of Firenze, Florence, Italy.

19 Institute of Genomic Medicine, Catholic University of the Sacred Heart, Rome, Italy.

20 Clinical Genetics, Kariminejad-Najmabadi Pathology & Genetics Research Center, Tehran, Iran.

21 Neurogenetics Division, Clinics Hospital of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

22 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.

23 Medical Genetics Unit, Department of Diagnosis, Pathology and Treatments of High Technological Complexity, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

24 Department of Neurosciences Drugs and Child Health, University of Florence, Florence, Italy.

25 Child Neuropsychiatry, ULSS 7 Pedemontana, Vicenza, Italy.

26 Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

27 Department of Neurosciences, University of Padua, Padua, Italy.

28 Neurology Department, San Camillo Hospital, Rome, Italy.

29 Metabolic and Muscular Unit, Neuroscience Department, Meyer Children’s Hospital, Florence, Italy.

30 First Department of Pediatrics, Aghia Sophia Children’s Hospital, University of Athens, Athens, Greece.

31 Clinical Genetics Service and South Tyrol Coordination Center for Rare Diseases, Department of Pediatrics, Regional Hospital of Bolzano, Bolzano, Italy.


1 comment

  1. Hi

    I was clinically diagnosed with HSP in 2010, blood tests taken at that time could not reveal the type of HSP I had. In 2018, at the insistence of my children (who wanted to know whether or not they had the illness), I was re-blood tested, and with the increased knowledge now of the defective genes, I was diagnosed with SPG7. The defective genes are (Gly352fs) and (Ala510Val).

    * On behalf of my family and I, I would like to thank those researchers, not only has their work helped me in this journey of living with HSP, but the knowledge gained by them has been most beneficial to my family!

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