Molecular Diagnosis in a Specialised Neurogenetic Clinic With Access to Whole-Genome Sequencing

Abstract

Background

Rare diseases, collectively affecting 1 in 17 people in the United Kingdom and Ireland, require coordinated care. Specialised multidisciplinary clinics offer a streamlined approach for diagnosis and management of rare neurogenetic disorders. The neurogenetic clinic at the National Hospital for Neurology and Neurosurgery (NHNN) provides a comprehensive service, incorporating whole-genome sequencing (WGS). This study was aimed at characterising the clinic′s patient population, assessing the proportion with a confirmed molecular diagnosis and determining the percentage requiring disease-specific surveillance or receiving precision treatment.

Methods

A retrospective review of consecutive patients attending the NHNN neurogenetic clinic from January to April 2022 captured data on phenotypes, genotypes, diagnostic methods and management strategies.

Results

Of 208 attendees (mean age 46.6 years; range 16–81 years), 182 exhibited neurological signs or symptoms, while 26 were referred for predictive testing. The predominant phenotypes were spastic paraplegia (28%), ataxia (22%) and neuromuscular presentations (16.5%). The molecular diagnosis rate among affected families was 59.1% (107/181). Among patients with a genetic diagnosis, 29.6% (32/108) were established through WGS-based panels since 2016. Almost 15% required coordinated multisystem surveillance. While many received symptomatic treatments, only one patient, with homozygous variants in ADCK3, received what could be considered precision treatment (coenzyme Q10). Three patients with severe neurogenetic disorders died prematurely, highlighting the pressing need for therapeutic advancement.

Conclusions

The ‘general’ neurogenetics clinic supports a highly diverse patient group, with most symptomatic patients achieving a molecular diagnosis, though many remain unsolved despite access to advanced genomic testing. The clinic plays a key role in coordinating multisystem surveillance and facilitating access to appropriate therapies. While precision treatments remain limited, recent gene therapy developments offer optimism, and accurately genotyped patients will be best positioned to benefit from therapeutic advances.