New genotype – phenotype correlations found in paediatric HSP

Posted - June 2018 in Living with HSP - Management & Treatment News

Warning on imitations of current methodologies

 

Genetic diagnosis was confirmed in 62% of children in this study, mostly with complicated HSP – a significantly higher than normal percentage.

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New genotype – phenotype correlations were found in several of the genes identified, but caution was expressed regarding the choice of genetic testing technology, with the decision best based on clinical suspicion.

 

Abstract

Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients.

 

To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection.

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Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had a clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A.

 

In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield.

 

Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion.

 

SOURCE: Neurogenetics. 2018 May;19(2):111-121. doi: 10.1007/s10048-018-0545-9. Epub 2018 Apr 24. PMID: 29691679

 

The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes.

 

Travaglini L1,2, Aiello C1,2, Stregapede F1,3, D’Amico A1,2, Alesi V4, Ciolfi A2, Bruselles A5, Catteruccia M1,2, Pizzi S2, Zanni G1,2, Loddo S4, Barresi S2, Vasco G6, Tartaglia M2, Bertini E7,8, Nicita F9,10.

 

1 Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, Polo di Ricerca S. Paolo, V.le S. Paolo, 15, 00146, Rome, Italy.

2 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

3 Department of Sciences, Roma Tre University, Rome, Italy.

4 Clinical Genetics, Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

5 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

6 Movement Analysis and Robotics Laboratory (MARLab), Neurorehabilitation Unit, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

7 Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, Polo di Ricerca S. Paolo, V.le S. Paolo, 15, 00146, Rome, Italy. [email protected]

8 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy. [email protected]

9 Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, Polo di Ricerca S. Paolo, V.le S. Paolo, 15, 00146, Rome, Italy. [email protected]

10 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy. [email protected]

 

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