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Homozygosity mapping and whole exome sequencing reveal a novel homozygous COL18A1 mutation causing Knobloch syndrome.

Haghighi A, Tiwari A, Piri N, Nürnberg G, Saleh-Gohari N, Haghighi A, Neidhardt J, Nürnberg P, Berger W - PLoS ONE (2014)

Bottom Line: Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient.The mutation was not present in SNP databases and was also not found in 192 control individuals.Its localization within the endostatin domain implicates a functional relevance of endostatin in KS.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, MA, United States of America; Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, United States of America.

ABSTRACT
The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients' DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.

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Related in: MedlinePlus

a. Pedigree of a consanguineous family initially diagnosed with chorioretinal degeneration and high myopia (in some family members). b. Color fundus photo OD shows the diffuse chorioretinal atrophy (white arrow points to the arterial narrowing). c. Color fundus photo OS showing the waxy optic disc (white arrow) and the well-circumscribed macular atrophic lesion (arrowhead). d. Flash ERG OU demonstrates severely diminished amplitudes of the a and b waves.
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pone-0112747-g001: a. Pedigree of a consanguineous family initially diagnosed with chorioretinal degeneration and high myopia (in some family members). b. Color fundus photo OD shows the diffuse chorioretinal atrophy (white arrow points to the arterial narrowing). c. Color fundus photo OS showing the waxy optic disc (white arrow) and the well-circumscribed macular atrophic lesion (arrowhead). d. Flash ERG OU demonstrates severely diminished amplitudes of the a and b waves.

Mentions: The female proband (IV-1, Figure 1a) was examined at 10 years of age. She initially presented at eight months of age with deviation and involuntary eye movements. On physical examination, at the first visit, she had nystagmus and esotropia, and normal anterior segment oculus uterque (both eyes, OU) [specifically speaking iris was normal OU and after pupillary dilation there was no abnormality in lens periphery OU]. Cycloplegic refraction revealed highly myopic refractive error OU (−16.00 D). Dilated fundus examination showed waxy optic discs (Figure 1c-white arrow) with a cup-to-disc ratio of 0.1, arterial narrowing (Figure 1b-white arrow) and a diffuse chorioretinal atrophy with a well-defined central atrophic lesion in the center of the macula OU (Figure 1c-arrowhead).


Homozygosity mapping and whole exome sequencing reveal a novel homozygous COL18A1 mutation causing Knobloch syndrome.

Haghighi A, Tiwari A, Piri N, Nürnberg G, Saleh-Gohari N, Haghighi A, Neidhardt J, Nürnberg P, Berger W - PLoS ONE (2014)

a. Pedigree of a consanguineous family initially diagnosed with chorioretinal degeneration and high myopia (in some family members). b. Color fundus photo OD shows the diffuse chorioretinal atrophy (white arrow points to the arterial narrowing). c. Color fundus photo OS showing the waxy optic disc (white arrow) and the well-circumscribed macular atrophic lesion (arrowhead). d. Flash ERG OU demonstrates severely diminished amplitudes of the a and b waves.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231049&req=5

pone-0112747-g001: a. Pedigree of a consanguineous family initially diagnosed with chorioretinal degeneration and high myopia (in some family members). b. Color fundus photo OD shows the diffuse chorioretinal atrophy (white arrow points to the arterial narrowing). c. Color fundus photo OS showing the waxy optic disc (white arrow) and the well-circumscribed macular atrophic lesion (arrowhead). d. Flash ERG OU demonstrates severely diminished amplitudes of the a and b waves.
Mentions: The female proband (IV-1, Figure 1a) was examined at 10 years of age. She initially presented at eight months of age with deviation and involuntary eye movements. On physical examination, at the first visit, she had nystagmus and esotropia, and normal anterior segment oculus uterque (both eyes, OU) [specifically speaking iris was normal OU and after pupillary dilation there was no abnormality in lens periphery OU]. Cycloplegic refraction revealed highly myopic refractive error OU (−16.00 D). Dilated fundus examination showed waxy optic discs (Figure 1c-white arrow) with a cup-to-disc ratio of 0.1, arterial narrowing (Figure 1b-white arrow) and a diffuse chorioretinal atrophy with a well-defined central atrophic lesion in the center of the macula OU (Figure 1c-arrowhead).

Bottom Line: Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient.The mutation was not present in SNP databases and was also not found in 192 control individuals.Its localization within the endostatin domain implicates a functional relevance of endostatin in KS.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, MA, United States of America; Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA, United States of America.

ABSTRACT
The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients' DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the COL18A1 gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in COL18A1 are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the COL18A1 gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.

Show MeSH
Related in: MedlinePlus