Limits...
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

Pedigree illustrating multiple instances of consanguinity. Patient 1 (V-3), the proband, is indicated with an arrow. The proband's parents (IV-4 and IV-5) shared a common grandfather approximately 5 generations ago. Individual's clinical phenotypes are specified according to the key. The individuals in the inset are related to both the maternal and paternal lineages, but exact relationships are not known.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664784&req=5

fig1: Pedigree illustrating multiple instances of consanguinity. Patient 1 (V-3), the proband, is indicated with an arrow. The proband's parents (IV-4 and IV-5) shared a common grandfather approximately 5 generations ago. Individual's clinical phenotypes are specified according to the key. The individuals in the inset are related to both the maternal and paternal lineages, but exact relationships are not known.

Mentions: Family history for both patients is significant for multiple instances of consanguinity throughout the pedigree and several family members were significant for infertility (Figure 1). Patients 1 and 2 have a 21-year-old brother (V-1) and 4 sisters ranging in age from 2 to 15 years of age who are all healthy with normal pubertal development, hair, and cognition (V-4 to V-7). The parents of our patients entered puberty at 16 years of age and they are at average height (180 cm and 158 cm) with normal hair, cognitive development, and fertility. There are 2 paternal aunts (IV-2 and IV-3) who underwent infertility treatment (i.e., IVF, hormone treatment) to conceive additional pregnancies after initial successful spontaneous gestations; one paternal aunt (IV-3) also has a history of hair loss. The paternal grandmother (III-2) carries a diagnosis of dementia since 65 years of age, complicated by a Parkinson-like movement disorder; she conceived all her pregnancies naturally per available history. The paternal grandfather (III-1) died at 64 years of age from lung cancer though he was not a smoker. The mother of our patients (IV-5) is alive and well with 8 full brothers, 3 full sisters, and 6 paternal half-siblings. There is a maternal cousin once-removed from our patients (IV-6) who never entered puberty and has hair loss and cognitive delay and another maternal second cousin (V-8) without pubertal development and difficulty in school. There are several distant cousins (multiple siblings sharing the same mother and father, V-9 to V-11) related through both the maternal and paternal sides of our patients who are described to have a similar body shape as patient 1, did not develop secondary sexual characteristics, and were infertile. The father of one of these affected family branches (IV-10) remarried and had several subsequent children with normal pubertal development.


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)

Pedigree illustrating multiple instances of consanguinity. Patient 1 (V-3), the proband, is indicated with an arrow. The proband's parents (IV-4 and IV-5) shared a common grandfather approximately 5 generations ago. Individual's clinical phenotypes are specified according to the key. The individuals in the inset are related to both the maternal and paternal lineages, but exact relationships are not known.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Pedigree illustrating multiple instances of consanguinity. Patient 1 (V-3), the proband, is indicated with an arrow. The proband's parents (IV-4 and IV-5) shared a common grandfather approximately 5 generations ago. Individual's clinical phenotypes are specified according to the key. The individuals in the inset are related to both the maternal and paternal lineages, but exact relationships are not known.
Mentions: Family history for both patients is significant for multiple instances of consanguinity throughout the pedigree and several family members were significant for infertility (Figure 1). Patients 1 and 2 have a 21-year-old brother (V-1) and 4 sisters ranging in age from 2 to 15 years of age who are all healthy with normal pubertal development, hair, and cognition (V-4 to V-7). The parents of our patients entered puberty at 16 years of age and they are at average height (180 cm and 158 cm) with normal hair, cognitive development, and fertility. There are 2 paternal aunts (IV-2 and IV-3) who underwent infertility treatment (i.e., IVF, hormone treatment) to conceive additional pregnancies after initial successful spontaneous gestations; one paternal aunt (IV-3) also has a history of hair loss. The paternal grandmother (III-2) carries a diagnosis of dementia since 65 years of age, complicated by a Parkinson-like movement disorder; she conceived all her pregnancies naturally per available history. The paternal grandfather (III-1) died at 64 years of age from lung cancer though he was not a smoker. The mother of our patients (IV-5) is alive and well with 8 full brothers, 3 full sisters, and 6 paternal half-siblings. There is a maternal cousin once-removed from our patients (IV-6) who never entered puberty and has hair loss and cognitive delay and another maternal second cousin (V-8) without pubertal development and difficulty in school. There are several distant cousins (multiple siblings sharing the same mother and father, V-9 to V-11) related through both the maternal and paternal sides of our patients who are described to have a similar body shape as patient 1, did not develop secondary sexual characteristics, and were infertile. The father of one of these affected family branches (IV-10) remarried and had several subsequent children with normal pubertal development.

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