Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations

Abstract

Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

Fig. 1. Genetic tools and geographical origins.

Genetic tools used for investigating our families and their utility (A) and the geographical origin of the families (B). A More than one genetic diagnostic approach was used in 23 out of 38 families, including all the undiagnosed families. Twenty-six families were investigated initially using HSP-targeted NGS gene panel (HSP panel) screening. Of these, eleven families were further investigated using WES and eight using WES and array genotyping. Eleven other families were directly investigated using WES, without HSP panel screening. Candidate gene approach was used in three families, two that were screened for repeat expansion-associated autosomal dominant spinocerebellar ataxias, and one for Friedreich’s ataxia repeat expansion. Sanger sequencing (not shown) was used for testing the segregation of all the identified candidate variants, except repeats expansion variants. HSP panel, hereditary spastic paraplegia next-generation sequencing targeted gene panel; WES, whole-exome sequencing. The families partially diagnosed relate to families where only a fraction of the patients was diagnosed. The numbers on the y-axis indicate the number of families; the filled circles indicate the used genetic tool. B The figure shows regions, states, or cities in Sudan from which the studied families originated (each pin-drop represents a single family).

Fig. 2. Clinical overview of the cohort.

A Patients’ age-at-examination. The mean age-at-examination was 17.2 years. B Age-at-onset of the SCDs in our patients. The mean age-at-onset was 7.54 years. C Signs detected during patients’ examination. The percentages of patients with pyramidal and cerebellar signs are shown. The majority of our patients presented with pyramidal features. D Features complicating the SCDs phenotype in our cohort. Skeletal deformities, intellectual impairment, and developmental delay and/or regression are the most common features complicating the SCDs phenotype in our cohort.

Fig. 3. The pattern of inheritance in the families with mutations in known disease genes.

Compound heterozygous inheritance is separated from homozygous autosomal recessive inheritance to highlight the effect of consanguinity. One family, F79, was counted in two inheritance modes as it segregated two likely causative variants with different patterns of inheritance but both possibly contributing to the phenotype as we reported previously (Ref. 19).