eP069: Possible founder variant and spectrum of phenotypic manifestation of Fukuyama muscular dystrophy reported in four unrelated Pakistani families

Document Type



Paediatrics and Child Health; Neurology


Background: Monogenic Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous group of disorders with about 500 associated genes. NMDs may be inherited in autosomal recessive, autosomal dominant and X-linked fashion. In the context of highly consanguineous Pakistani population, we expect the autosomal recessive NMDs to have a higher prevalence, compared to that seen in the populations with European ancestry. However, we do not have contextual ethno-specific genomics data for NMDs in Pakistani population. Next Generation Sequencing (NGS) has revolutionized the diagnostic practice for NMDs, having the ability to simultaneously capture and sequence multiple genes with disease-specific gene panels, sequence the coding portion of the human genome with whole exome sequencing (WES) or the entire genome with whole genome sequencing (WGS). With this becoming a clinical practice to integrate genomic testing in offering diagnosis; the challenge of diagnostic odyssey is diminishing. From the broad spectrum of hereditary NMDs, dystroglycanopathies are heterogenous group of disorders that typically manifest as limb-girdle muscular weakness. About 18 genes are now known to be associated with dystroglycanopathies, these genes encode proteins that function as a modulator for the binding of α-dystroglycan to the extracellular matrix ligands by glycosylation alternation. As a result of which, the structural integrity of the myocytes is disrupted, subsequently leading to muscle degeneration. FKTN is one of the genes associate with dystroglycanopathies, it encodes for a glycosyltransferase.
Case presentation: We report four unrelated families of FKTN associated autosomal recessive Fukuyama Muscular Dystrophy (MIM:613152), from a diverse Pakistani patient population seen at a Tertiary Healthcare Centre, in Karachi Pakistan. All four patients harbored homozygous, well-established pathogenic missense variant, FKTN, NM_001079802.1:c.920G>A (p.Arg307Gln), (gnomAD MAF 0.001204%, rs119463992). This variant has been previously reported in multiple Turkish families in homozygous state, and one multi-ethnic (half Jewish and half Indian) family with another variant found in compound heterozygous state. At large, about half of the cases of FKTN associated muscular dystrophy are reported with severe brain involvement; clinically manifesting as intellectual disability and seizure disorder. Consistent with the genotype-phenotype correlation, the protein-truncating variants result in a more severe phenotype than missense variants. In our reported cases, the variant has showed a spectrum of phenotype with variable symptom onset age (between age of 2-16 years); in patients belonging to different regions of the country. However, it is not reported to be associated with intellectual disability and seizure disorder. In the previously reported cases for this variant, cardiac involved has not been mentioned. Additionally, three out of four patients from our center, presented with dilated cardiomyopathy which progressive reduction in the left-ventricular ejection fraction (LV EF), while for the fourth patient an echocardiogram was not present. The clinical details from four, unrelated families are described in Table 1.
Conclusion: We report four unrelated Pakistani families from ethnically diverse backgrounds, harboring similar pathogenic variant in FKTN, which is likely to be a founder variant, in South Asian and Middle Eastern ethnic groups. In these cases, the age of first symptom manifestation was variable, however all began with motor delays or difficulties. The dilated cardiomyopathy was a saliant feature, observed in three patients, that can lead to initiating cardiac screening in patients harboring this variant, at a younger age. Consistent with previous work, the symptom severity in the reported missense variant was mild, compared with protein-truncating variants, which is accompanied with severe brain involvement. As NMDs are further characterized in Pakistani populations, our knowledge of ethno-specific FTKN variants and their genotype-phenotype correlations will be better elucidated.

Publication (Name of Journal)

Genetics in Medicine