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The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome.

Sheridan MB, Wohler E, Batista DA, Applegate C, Hoover-Fong J - Case Rep Genet (2015)

Bottom Line: Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC).Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation.This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.

View Article: PubMed Central - PubMed

Affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

ABSTRACT
Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.

No MeSH data available.


Related in: MedlinePlus

Illumina HumanOmni1-Quad SNP array indicates a shared region of homozygosity on chromosome 2q31.1. This region is approximately 2.9 Mb and contains DCAF17, the gene associated with WSS. This graphic was constructed using the UCSC Genome Browser (GRCh37/hg19).
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fig2: Illumina HumanOmni1-Quad SNP array indicates a shared region of homozygosity on chromosome 2q31.1. This region is approximately 2.9 Mb and contains DCAF17, the gene associated with WSS. This graphic was constructed using the UCSC Genome Browser (GRCh37/hg19).

Mentions: Based on the highly suggestive autosomal recessive pedigree, we performed a SNP array on patients 1 and 2 to examine shared areas of homozygosity for genes associated with HH. The SNP arrays revealed a male genotype and female genotype with no significant copy number alterations for patients 1 and 2, respectively. However, as expected due to the consanguineous family history, in each individual there were multiple, large homozygous regions (>1 Mb in length) with normal copy number. These homozygous regions ranged in size from 1 Mb to 12.5 Mb and represented approximately 2.8% of the genome in each patient. Overall, the two siblings shared 10 homozygous regions totaling to 30.5 Mb (0.99% of genome). The Genomic Oligoarray and SNP array evaluation tool v3.0 (http://firefly.ccs.miami.edu/cgi-bin/ROH/ROH_analysis_tool.cgi) was used to search for genes associated with HH in the shared regions of homozygosity [17]. A search of OMIM Clinical Synopsis fields using the term “hypogonadism” identified DCAF17 as the only candidate gene in the shared regions of homozygosity (Figure 2). Sequencing of the coding exons and flanking intronic regions of DCAF17 in patient 1 revealed homozygosity for the previously described founder mutation (c.436delC; p.Ala147Hisfs∗9) [6]. Targeted DCAF17 sequencing in patient 2 identified the same homozygous mutation. Monetary resources were not available to confirm the heterozygous carrier status of the parents. However, as noted, this family's DCAF17 mutation was previously described, there was no evidence of a large DCAF17 deletion, and our patients' phenotype was consistent with WSS.


The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome.

Sheridan MB, Wohler E, Batista DA, Applegate C, Hoover-Fong J - Case Rep Genet (2015)

Illumina HumanOmni1-Quad SNP array indicates a shared region of homozygosity on chromosome 2q31.1. This region is approximately 2.9 Mb and contains DCAF17, the gene associated with WSS. This graphic was constructed using the UCSC Genome Browser (GRCh37/hg19).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664784&req=5

fig2: Illumina HumanOmni1-Quad SNP array indicates a shared region of homozygosity on chromosome 2q31.1. This region is approximately 2.9 Mb and contains DCAF17, the gene associated with WSS. This graphic was constructed using the UCSC Genome Browser (GRCh37/hg19).
Mentions: Based on the highly suggestive autosomal recessive pedigree, we performed a SNP array on patients 1 and 2 to examine shared areas of homozygosity for genes associated with HH. The SNP arrays revealed a male genotype and female genotype with no significant copy number alterations for patients 1 and 2, respectively. However, as expected due to the consanguineous family history, in each individual there were multiple, large homozygous regions (>1 Mb in length) with normal copy number. These homozygous regions ranged in size from 1 Mb to 12.5 Mb and represented approximately 2.8% of the genome in each patient. Overall, the two siblings shared 10 homozygous regions totaling to 30.5 Mb (0.99% of genome). The Genomic Oligoarray and SNP array evaluation tool v3.0 (http://firefly.ccs.miami.edu/cgi-bin/ROH/ROH_analysis_tool.cgi) was used to search for genes associated with HH in the shared regions of homozygosity [17]. A search of OMIM Clinical Synopsis fields using the term “hypogonadism” identified DCAF17 as the only candidate gene in the shared regions of homozygosity (Figure 2). Sequencing of the coding exons and flanking intronic regions of DCAF17 in patient 1 revealed homozygosity for the previously described founder mutation (c.436delC; p.Ala147Hisfs∗9) [6]. Targeted DCAF17 sequencing in patient 2 identified the same homozygous mutation. Monetary resources were not available to confirm the heterozygous carrier status of the parents. However, as noted, this family's DCAF17 mutation was previously described, there was no evidence of a large DCAF17 deletion, and our patients' phenotype was consistent with WSS.

Bottom Line: Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC).Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation.This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.

View Article: PubMed Central - PubMed

Affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

ABSTRACT
Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.

No MeSH data available.


Related in: MedlinePlus