Haplotype-Phenotype correlation in Fukuyama congenital muscular dystrophy

Abstract

In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor function is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinically difficult to differentiate this severe FCMD from Walker-Warburg syndrome (WWS) or from muscle-eye-brain disease (MEBD). In order to establish a genotype-phenotype correlation, we performed haplotype analysis using microsatellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype. In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmological abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype are heterozygous for the A-F haplotype, and the other one homozygous for the haplotype. We confirmed that at least one chromosome in each of the 56 FCMD patients has the A-F haplotype. The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation. Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD.

Target resequencing of neuromuscular disease-related genes using next-generation sequencing for patients with undiagnosed early-onset neuromuscular disorders

“…[29][30][31] We identified point mutations in the FKTN gene in four patients. In MD-1, we identified an intronic mutation that is specific to the Korean population.…”

Structural organization, complete genomic sequences and mutational analyses of the Fukuyama‐type congenital muscular dystrophy gene, fukutin

“…Walker–Warburg syndrome (WWS) and muscle–eye–brain disease are well known congenital muscular dystrophies that also involve central nervous system abnormalities and ocular malformations [12–15]. Although both syndromes are generally more severe than FCMD, it is sometimes difficult to distinguish severe FCMD from WWS clinically [16–18]. In a recent study, we used sequence data presented here to identify four novel mutations in rare alleles.…”

Functions of Fukutin, a Gene Responsible for Fukuyama Type Congenital Muscular Dystrophy, in Neuromuscular System and Other Somatic Organs

“…Some cases are heterozygous for founder haplotype, carrying the founder mutation and a mutation other than the founder mutation. Severe FCMD cases tend to be heterozygous for founder haplotype [25]. Homozygous mutation (not a founder mutation) of fukutin is found to be lethal for mice embryo, and fukutin is considered to be essential for early embryonic development in mice [26].…”