Limits...
Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos.

Khorram D, Choi M, Roos BR, Stone EM, Kopel T, Allen R, Alward WL, Scheetz TE, Fingert JH - Mol. Vis. (2015)

Bottom Line: Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications.Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members.Neither TMEM98 mutation was detected in public exome sequence databases.

View Article: PubMed Central - PubMed

Affiliation: Marianas Eye Institute, Saipan, Northern Mariana Islands.

ABSTRACT

Purpose: Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees.

Methods: Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene.

Results: Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.

Conclusions: A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

No MeSH data available.


Related in: MedlinePlus

Nanophthalmos pedigree 991-F from the United States. Subjects with nanophthalmos are indicated with black symbols, while healthy subjects are indicated with white symbols. Gray symbols indicate unknown affection status. Diagnosis was made with a clinical exam or a review of the medical records for all available family members. Diagnosis of family members indicated with stars was determined by family history. The subjects who contributed a DNA sample for the study are indicated with an “X.”
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4556162&req=5

f1: Nanophthalmos pedigree 991-F from the United States. Subjects with nanophthalmos are indicated with black symbols, while healthy subjects are indicated with white symbols. Gray symbols indicate unknown affection status. Diagnosis was made with a clinical exam or a review of the medical records for all available family members. Diagnosis of family members indicated with stars was determined by family history. The subjects who contributed a DNA sample for the study are indicated with an “X.”

Mentions: Research was approved by local Internal Review Boards and all patients provided written consent in advance of the study. The study design met the tenets of the Declaration of Helsinki and Association for Research in Vision and Ophthalmology guidelines. Participants were examined by an ophthalmologist and underwent an eye examination that included measurement of visual acuity, refractive error, and intraocular pressure as well as a slit-lamp examination of the anterior chamber and fundus examination. Axial eye length was measured in some patients with A-scan ultrasound (Alcon, Fort Worth, TX). Patients were diagnosed with nanophthalmos when short axial eye length (<20 mm) or significant hyperopia (spherical equivalent > +6.00) were observed in the absence of other ocular abnormalities. The control subjects showed no evidence of nanophthalmos. Some members of both pedigrees contributed DNA samples but were unavailable for examination, and medical records could not be obtained. These subjects are indicated on the pedigree drawing with stars (Figure 1), and their affection status was determined according to the family history report.


Novel TMEM98 mutations in pedigrees with autosomal dominant nanophthalmos.

Khorram D, Choi M, Roos BR, Stone EM, Kopel T, Allen R, Alward WL, Scheetz TE, Fingert JH - Mol. Vis. (2015)

Nanophthalmos pedigree 991-F from the United States. Subjects with nanophthalmos are indicated with black symbols, while healthy subjects are indicated with white symbols. Gray symbols indicate unknown affection status. Diagnosis was made with a clinical exam or a review of the medical records for all available family members. Diagnosis of family members indicated with stars was determined by family history. The subjects who contributed a DNA sample for the study are indicated with an “X.”
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556162&req=5

f1: Nanophthalmos pedigree 991-F from the United States. Subjects with nanophthalmos are indicated with black symbols, while healthy subjects are indicated with white symbols. Gray symbols indicate unknown affection status. Diagnosis was made with a clinical exam or a review of the medical records for all available family members. Diagnosis of family members indicated with stars was determined by family history. The subjects who contributed a DNA sample for the study are indicated with an “X.”
Mentions: Research was approved by local Internal Review Boards and all patients provided written consent in advance of the study. The study design met the tenets of the Declaration of Helsinki and Association for Research in Vision and Ophthalmology guidelines. Participants were examined by an ophthalmologist and underwent an eye examination that included measurement of visual acuity, refractive error, and intraocular pressure as well as a slit-lamp examination of the anterior chamber and fundus examination. Axial eye length was measured in some patients with A-scan ultrasound (Alcon, Fort Worth, TX). Patients were diagnosed with nanophthalmos when short axial eye length (<20 mm) or significant hyperopia (spherical equivalent > +6.00) were observed in the absence of other ocular abnormalities. The control subjects showed no evidence of nanophthalmos. Some members of both pedigrees contributed DNA samples but were unavailable for examination, and medical records could not be obtained. These subjects are indicated on the pedigree drawing with stars (Figure 1), and their affection status was determined according to the family history report.

Bottom Line: Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications.Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members.Neither TMEM98 mutation was detected in public exome sequence databases.

View Article: PubMed Central - PubMed

Affiliation: Marianas Eye Institute, Saipan, Northern Mariana Islands.

ABSTRACT

Purpose: Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees.

Methods: Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene.

Results: Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases.

Conclusions: A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.

No MeSH data available.


Related in: MedlinePlus