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Evidence for additional FREM1 heterogeneity in Manitoba oculotrichoanal syndrome.

Mateo RK, Johnson R, Lehmann OJ - Mol. Vis. (2012)

Bottom Line: Subsequent sequencing of both genes in the IBD region, followed by FREM1, did not reveal any mutations.This study illustrates the utility of studying geographically isolated populations to identify genomic regions responsible for disease through analysis of small numbers of affected individuals.The location of the IBD region 16 kb from FREM1 suggests the phenotype in these patients is attributable to a variant outside of FREM1, potentially in a regulatory element, whose identification may prove tractable to next generation sequencing.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada. robertin@ualberta.ca

ABSTRACT

Purpose: Manitoba Oculotrichoanal (MOTA) syndrome is an autosomal recessive disorder present in First Nations families that is characterized by ocular (cryptophthalmos), facial, and genital anomalies. At the commencement of this study, its genetic basis was undefined.

Methods: Homozygosity analysis was employed to map the causative locus using DNA samples from four probands of Cree ancestry. After single nucleotide polymorphism (SNP) genotyping, data were analyzed and exported to PLINK to identify regions identical by descent (IBD) and common to the probands. Candidate genes within and adjacent to the IBD interval were sequenced to identify pathogenic variants, with analyses of potential deletions or duplications undertaken using the B-allele frequency and log(2) ratio of SNP signal intensity.

Results: Although no shared IBD region >1 Mb was evident on preliminary analysis, adjusting the criteria to permit the detection of smaller homozygous IBD regions revealed one 330 Kb segment on chromosome 9p22.3 present in all 4 probands. This interval comprising 152 SNPs, lies 16 Kb downstream of FRAS1-related extracellular matrix protein 1 (FREM1), and no copy number variations were detected either in the IBD region or FREM1. Subsequent sequencing of both genes in the IBD region, followed by FREM1, did not reveal any mutations.

Conclusions: This study illustrates the utility of studying geographically isolated populations to identify genomic regions responsible for disease through analysis of small numbers of affected individuals. The location of the IBD region 16 kb from FREM1 suggests the phenotype in these patients is attributable to a variant outside of FREM1, potentially in a regulatory element, whose identification may prove tractable to next generation sequencing. In the context of recent identification of FREM1 coding mutations in a proportion of MOTA cases, characterization of such additional variants offers scope both to enhance understanding of FREM1's role in cranio-facial biology and may facilitate genetic counselling in populations with high prevalences of MOTA to reduce the incidence of this disorder.

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Related in: MedlinePlus

MOTA phenotypic spectrum in Albertan First Nations pedigrees. The oculo-facial phenotypes observed are diverse, ranging from isolated ocular anomalies to broader characteristics including dimpled noses (white arrows) and aberrant hair wedges where hair extends across the forehead to reach the eyebrow (black arrows). As evident from the montage, the ocular malformations can be bilateral (A, B) or unilateral (C, D), and vary in terms of the degree of lid involvement from isolated fusion (D) to abortive cryptophthalmos (E). Associated features include corneopalpebral synechiae (E, F), corneal opacification (G), and vascularization (H).
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f2: MOTA phenotypic spectrum in Albertan First Nations pedigrees. The oculo-facial phenotypes observed are diverse, ranging from isolated ocular anomalies to broader characteristics including dimpled noses (white arrows) and aberrant hair wedges where hair extends across the forehead to reach the eyebrow (black arrows). As evident from the montage, the ocular malformations can be bilateral (A, B) or unilateral (C, D), and vary in terms of the degree of lid involvement from isolated fusion (D) to abortive cryptophthalmos (E). Associated features include corneopalpebral synechiae (E, F), corneal opacification (G), and vascularization (H).

Mentions: The four MOTA cases displayed a spectrum of ocular anomalies with considerable variation in phenotypic severity. There was a greater proportion of bilateral (n=3) than unilateral involvement (Figure 2), and cases with partial upper eyelid involvement most frequently affected the medial segment. Additional features included fusion of the eyelid to the cornea, which ranged in severity from total fusion (Figure 2D) to focal synechiae (Figure 2E,F), as well as frequent corneal opacification and corneal vascularisation (Figure 2G,H). Aberrant facial development was evident from extension of hair distribution from the scalp to reach the eyebrow (Figure 2B,C) as well as nasal dimpling (Figure 2B,D).


Evidence for additional FREM1 heterogeneity in Manitoba oculotrichoanal syndrome.

Mateo RK, Johnson R, Lehmann OJ - Mol. Vis. (2012)

MOTA phenotypic spectrum in Albertan First Nations pedigrees. The oculo-facial phenotypes observed are diverse, ranging from isolated ocular anomalies to broader characteristics including dimpled noses (white arrows) and aberrant hair wedges where hair extends across the forehead to reach the eyebrow (black arrows). As evident from the montage, the ocular malformations can be bilateral (A, B) or unilateral (C, D), and vary in terms of the degree of lid involvement from isolated fusion (D) to abortive cryptophthalmos (E). Associated features include corneopalpebral synechiae (E, F), corneal opacification (G), and vascularization (H).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369896&req=5

f2: MOTA phenotypic spectrum in Albertan First Nations pedigrees. The oculo-facial phenotypes observed are diverse, ranging from isolated ocular anomalies to broader characteristics including dimpled noses (white arrows) and aberrant hair wedges where hair extends across the forehead to reach the eyebrow (black arrows). As evident from the montage, the ocular malformations can be bilateral (A, B) or unilateral (C, D), and vary in terms of the degree of lid involvement from isolated fusion (D) to abortive cryptophthalmos (E). Associated features include corneopalpebral synechiae (E, F), corneal opacification (G), and vascularization (H).
Mentions: The four MOTA cases displayed a spectrum of ocular anomalies with considerable variation in phenotypic severity. There was a greater proportion of bilateral (n=3) than unilateral involvement (Figure 2), and cases with partial upper eyelid involvement most frequently affected the medial segment. Additional features included fusion of the eyelid to the cornea, which ranged in severity from total fusion (Figure 2D) to focal synechiae (Figure 2E,F), as well as frequent corneal opacification and corneal vascularisation (Figure 2G,H). Aberrant facial development was evident from extension of hair distribution from the scalp to reach the eyebrow (Figure 2B,C) as well as nasal dimpling (Figure 2B,D).

Bottom Line: Subsequent sequencing of both genes in the IBD region, followed by FREM1, did not reveal any mutations.This study illustrates the utility of studying geographically isolated populations to identify genomic regions responsible for disease through analysis of small numbers of affected individuals.The location of the IBD region 16 kb from FREM1 suggests the phenotype in these patients is attributable to a variant outside of FREM1, potentially in a regulatory element, whose identification may prove tractable to next generation sequencing.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada. robertin@ualberta.ca

ABSTRACT

Purpose: Manitoba Oculotrichoanal (MOTA) syndrome is an autosomal recessive disorder present in First Nations families that is characterized by ocular (cryptophthalmos), facial, and genital anomalies. At the commencement of this study, its genetic basis was undefined.

Methods: Homozygosity analysis was employed to map the causative locus using DNA samples from four probands of Cree ancestry. After single nucleotide polymorphism (SNP) genotyping, data were analyzed and exported to PLINK to identify regions identical by descent (IBD) and common to the probands. Candidate genes within and adjacent to the IBD interval were sequenced to identify pathogenic variants, with analyses of potential deletions or duplications undertaken using the B-allele frequency and log(2) ratio of SNP signal intensity.

Results: Although no shared IBD region >1 Mb was evident on preliminary analysis, adjusting the criteria to permit the detection of smaller homozygous IBD regions revealed one 330 Kb segment on chromosome 9p22.3 present in all 4 probands. This interval comprising 152 SNPs, lies 16 Kb downstream of FRAS1-related extracellular matrix protein 1 (FREM1), and no copy number variations were detected either in the IBD region or FREM1. Subsequent sequencing of both genes in the IBD region, followed by FREM1, did not reveal any mutations.

Conclusions: This study illustrates the utility of studying geographically isolated populations to identify genomic regions responsible for disease through analysis of small numbers of affected individuals. The location of the IBD region 16 kb from FREM1 suggests the phenotype in these patients is attributable to a variant outside of FREM1, potentially in a regulatory element, whose identification may prove tractable to next generation sequencing. In the context of recent identification of FREM1 coding mutations in a proportion of MOTA cases, characterization of such additional variants offers scope both to enhance understanding of FREM1's role in cranio-facial biology and may facilitate genetic counselling in populations with high prevalences of MOTA to reduce the incidence of this disorder.

Show MeSH
Related in: MedlinePlus