Limits...
Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions.

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R - Genet. Med. (2014)

Bottom Line: Patients with undetermined causes were clinically reexamined and tested for copy-number variations as well as intronic mutations.Few ABCA4 mutations were observed in our French Canadian patients.This population may contain an unidentified founder mutation.

View Article: PubMed Central - PubMed

Affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

ABSTRACT

Purpose: Stargardt macular dystrophy (STGD) results in early central vision loss. We sought to explain the genetic cause of STGD in a cohort of 88 patients from three different cultural backgrounds.

Methods: Next-generation sequencing using a novel capture panel was used to search for disease-causing mutations. Patients with undetermined causes were clinically reexamined and tested for copy-number variations as well as intronic mutations.

Results: We determined the cause of disease in 67% of our patients. Our analysis identified 35 novel ABCA4 alleles. Eleven patients had mutations in genes not previously reported to cause STGD. Finally, 45% of our patients with unsolved causes had single deleterious mutations in ABCA4, a recessive disease gene. No likely pathogenic copy-number variations were identified.

Conclusion: This study expands our knowledge of STGD by identifying dozens of novel alleles that cause the disease. The frequency of single mutations in ABCA4 among STGD patients is higher than that among controls, indicating that these mutations contribute to disease. Disease in 11 patients was explained by mutations outside ABCA4, underlining the need to genotype all retinal disease genes to maximize genetic diagnostic rates. Few ABCA4 mutations were observed in our French Canadian patients. This population may contain an unidentified founder mutation. Our results indicate that copy-number variations are unlikely to be a major cause of STGD.

Show MeSH

Related in: MedlinePlus

Representative CGH microarray from a patient with one hit in ABCA4. Despite a very high probe density, no significant CNVs were found in any of the 12 patients with one mutation in ABCA4
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4385427&req=5

Figure 2: Representative CGH microarray from a patient with one hit in ABCA4. Despite a very high probe density, no significant CNVs were found in any of the 12 patients with one mutation in ABCA4

Mentions: Surprisingly, 13/29(45%) unsolved patients had a single observed likely pathogenic mutation in ABCA4 and no observed second ABCA4 mutation, which is significantly higher than the expected rate in the general population (5%). This effect had no significant variation between cohorts. To investigate whether copy number variations in ABCA4 could explain some of these unsolved cases, we performed chromosomal analysis on the 12 patients with a single heterozygous hit in ABCA4. No likely deleterious copy number variations were observed (fig 2). Those patients that were not solved following thorough analysis of ABCA4 were checked for mutations in other retinal disease genes based on capture sequence data. Eleven patients (13%) were solved invoking retinal disease genes not previously linked to STGD (table 1), bringing the total number of molecularly diagnosed patients to 59 (67%). Ten novel candidate disease causing mutations outside of ABCA4 were observed (table 1).


Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions.

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R - Genet. Med. (2014)

Representative CGH microarray from a patient with one hit in ABCA4. Despite a very high probe density, no significant CNVs were found in any of the 12 patients with one mutation in ABCA4
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385427&req=5

Figure 2: Representative CGH microarray from a patient with one hit in ABCA4. Despite a very high probe density, no significant CNVs were found in any of the 12 patients with one mutation in ABCA4
Mentions: Surprisingly, 13/29(45%) unsolved patients had a single observed likely pathogenic mutation in ABCA4 and no observed second ABCA4 mutation, which is significantly higher than the expected rate in the general population (5%). This effect had no significant variation between cohorts. To investigate whether copy number variations in ABCA4 could explain some of these unsolved cases, we performed chromosomal analysis on the 12 patients with a single heterozygous hit in ABCA4. No likely deleterious copy number variations were observed (fig 2). Those patients that were not solved following thorough analysis of ABCA4 were checked for mutations in other retinal disease genes based on capture sequence data. Eleven patients (13%) were solved invoking retinal disease genes not previously linked to STGD (table 1), bringing the total number of molecularly diagnosed patients to 59 (67%). Ten novel candidate disease causing mutations outside of ABCA4 were observed (table 1).

Bottom Line: Patients with undetermined causes were clinically reexamined and tested for copy-number variations as well as intronic mutations.Few ABCA4 mutations were observed in our French Canadian patients.This population may contain an unidentified founder mutation.

View Article: PubMed Central - PubMed

Affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA [2] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

ABSTRACT

Purpose: Stargardt macular dystrophy (STGD) results in early central vision loss. We sought to explain the genetic cause of STGD in a cohort of 88 patients from three different cultural backgrounds.

Methods: Next-generation sequencing using a novel capture panel was used to search for disease-causing mutations. Patients with undetermined causes were clinically reexamined and tested for copy-number variations as well as intronic mutations.

Results: We determined the cause of disease in 67% of our patients. Our analysis identified 35 novel ABCA4 alleles. Eleven patients had mutations in genes not previously reported to cause STGD. Finally, 45% of our patients with unsolved causes had single deleterious mutations in ABCA4, a recessive disease gene. No likely pathogenic copy-number variations were identified.

Conclusion: This study expands our knowledge of STGD by identifying dozens of novel alleles that cause the disease. The frequency of single mutations in ABCA4 among STGD patients is higher than that among controls, indicating that these mutations contribute to disease. Disease in 11 patients was explained by mutations outside ABCA4, underlining the need to genotype all retinal disease genes to maximize genetic diagnostic rates. Few ABCA4 mutations were observed in our French Canadian patients. This population may contain an unidentified founder mutation. Our results indicate that copy-number variations are unlikely to be a major cause of STGD.

Show MeSH
Related in: MedlinePlus