Four large families with infantile nystagmus were analyzed by linkage analysis. In family A (from the Sandong province), 16 of the 46 living family members are affected including 10 males and six females. In addition, three females are obligate unaffected carriers. No male-to-male transmission was observed. The proband is a nine-year-old girl (, individual IV12) who had nystagmus since three to four months after birth. She has a horizontal jerk ocular oscillation and a face turn to left with the null point to the right. The corrected visual acuity of both eyes at distance is 1.0. Her father is 32 years old with nystagmus since he was three to four months old. He has a horizontal ocular oscillation with a torsional component and with little head posture and head shaking. His corrected visual acuities for both eyes are 0.5. Other patients have various reduced visual acuity ranging from 0.2 to 1.0. Five of them have head posture, and two of them have head oscillations. The penetrance appears to be complete in males and about 60% in the females.
Figure 1 Pedigrees of seven families with X-linked congenital nystagmus. Squares indicate males, circles indicate females, slashed symbols indicate deceased, black symbols indicate affected individuals, unfilled symbols indicate unaffected individuals, and unaffected, (more ...)
Significant LOD scores were obtained with polymorphic markers DXS1047 (Zmax=8.55, θmax=0) and DXS1001 (Z max=5.55, θ max=0). Direct DNA sequence analysis from all patients and obligate carriers reveals a c. 812G>T missense mutation in exon 9, which would result in a substitution of the cysteine residue at codon 271 by a phenylalanine residue (C271F, ).
Figure 2 Sequencing results of affected heterozygous females from families A and D and of affected hemizygous males from families B, E, F, and G . Five types of FRMD7 mutations were identified in six families, which were c. 812G>T (p. C271F) in family (more ...)
In family B (from the Henan province), nine patients (three males and six females) show horizontal jerk ocular oscillation. The affected males have more serious ocular oscillation than the affected females. Five females are obligate unaffected carriers. The proband is a nine-year-old boy (individual IV2 in ) who developed nystagmus at three to four months of age with 0.7 corrected visual acuity in both eyes at distance. His mother is an asymptomatic obligate carrier. Other patients have various reduced visual acuity ranging from 0.4 to 1.0. A significant LOD Score of 3.61 (θmax=0) was obtained with polymorphic marker, DXS1047, and a LOD score of 2.03 (θmax=0.1) was obtained with DXS1001. Direct DNA sequence analysis of FRMD7 from all patients and obligate carriers revealed a 2 bp deletion (AG, 689–690) in exon 8 that was not present in unaffected family members (). The deletion is predicted to result in an aberrant truncated protein.
Family C was from Liaoning province, and 12 patients (six males and six females) in this family were found with horizontal jerk ocular oscillations but without head posture. Three females are obligate unaffected carriers. The proband is an eight-year-old boy (individual V7 in ) who developed nystagmus at three to four months of age with 0.3 corrected visual acuity of both eyes at distance. Other patients have various reduced visual acuity ranging from 0.2 to 1.0. Positive LOD scores of 2.42 (θmax=0.1) and 0.65 (θmax=0.25) were obtained with polymorphic markers, DXS1047 and DXS1001, respectively. No mutations were detected in the FRMD7 gene, although all coding regions and exon-intron boundaries were sequenced.
In Family D (from Wuhan province), eight patients (two males and six females) show horizontal jerk ocular oscillation. The proband is a nine-year-old boy (individual III5 in ), and his mother is the only asymptomatic obligate carrier in all the female members of this family. A positive LOD score of 1.57 (θmax=0) was obtained with polymorphic marker DXS1047, and a LOD score of 1.31 (θmax=0) was obtained with DXS1001. Sequence analysis revealed a c. 70G>T missense mutation in exon 2 in all patients and obligate carriers, which would result in a substitution of the glycine residue at codon 24 by a tryptophan residue ().
Families E and F are from Tianjin, and there is no indication by history that they are related. There is an insufficient number of available affected family members in these two families to provide a significant LOD score. A direct sequence of all affected patients in families E and F revealed the same sequence change in exon 9, a c. 782G>A missense mutation, which would result in substitution of the arginine residue at codon 260 by a glutamine residue (R260Q, ).
To examine the possibility of a common origin between families E and F, four single nucleotide polymorphisms (SNPs; rs2180237
, and rs2748724
) in and around FRMD7
were genotyped in affected males, individual II1
of family E and individual IV1
of family F (). The haplotypes of these two affected males and by extension that in their respective families is quite distinct. This suggests that the same mutation, R260Q, occurred independently in these two families rather than descending from a common ancestor.
Sequence analysis of four SNPs in two affected males from two families.
Sequence analysis of all patients and obligate carriers in family G revealed a c. 910C>T nonsense mutation in exon 10, which would result in substitution of the arginine residue at codon 303 by a stop codon (R303X, ).
The maximum LOD scores and mutations identified for each family are shown in . None of these five mutations were detected in 50 male and 50 female unaffected control individuals when tested by single strand conformation polymorphism (not shown). These results suggest that c.70 G>T (p.G24W) in exon 2, c.689–690delAG (p.Ser232del) in exon 8, c. 782G>A (p.R260Q) and c. 812G>T (p. C271F) in exon 9, and c. 910C>T (R303X) in exon 10 are novel mutations in the FRMD7 gene.
Mutations in seven families and the significant LOD score in four families.