TY - JOUR
T1 - The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome
AU - Quaynor, Samuel D.
AU - Kim, Hyung Goo
AU - Cappello, Elizabeth M.
AU - Williams, Tiera
AU - Chorich, Lynn P.
AU - Bick, David P.
AU - Sherins, Richard J.
AU - Layman, Lawrence C.
PY - 2011/12
Y1 - 2011/12
N2 - Objective: To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). Design: Molecular analysis of DNA in IHH/KS patients. Setting: Academic medical center. Patient(s): Twenty-four IHH/KS patients with a known mutation (group 1) and 24 IHH/KS patients with no known mutation (group 2). Intervention(s): DNA from IHH/KS patients was subjected to polymerase chain reaction-based DNA sequencing of the 13 most common genes (KAL1, GNRHR, FGFR1, KISS1R, TAC3, TACR3, FGF8, PROKR2, PROK2, CHD7, NELF, GNRH1, and WDR11). Main Outcome Measure(s): The identification of mutations absent in ≥188 ethnically matched controls. Both SIFT (sorting intolerant from tolerant) and conservation among orthologs provided supportive evidence for pathologic roles. Result(s): In group 1, 6 (25%) of 24 IHH/KS patients had a heterozygous mutation in a second gene, and in group 2, 13 (54.2%) of 24 had a mutation in at least one gene, but none had digenic mutations. In group 2, 7 (29.2%) of 24 had a mutation considered sufficient to cause the phenotype. Conclusion(s): When the 13 most common IHH/KS genes are studied, the overall prevalence of digenic gene mutations in IHH/KS was 12.5%. In addition, approximately 30% of patients without a known mutation had a mutation in a single gene. With the current state of knowledge, these findings suggest that most IHH/KS patients have a monogenic etiology.
AB - Objective: To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). Design: Molecular analysis of DNA in IHH/KS patients. Setting: Academic medical center. Patient(s): Twenty-four IHH/KS patients with a known mutation (group 1) and 24 IHH/KS patients with no known mutation (group 2). Intervention(s): DNA from IHH/KS patients was subjected to polymerase chain reaction-based DNA sequencing of the 13 most common genes (KAL1, GNRHR, FGFR1, KISS1R, TAC3, TACR3, FGF8, PROKR2, PROK2, CHD7, NELF, GNRH1, and WDR11). Main Outcome Measure(s): The identification of mutations absent in ≥188 ethnically matched controls. Both SIFT (sorting intolerant from tolerant) and conservation among orthologs provided supportive evidence for pathologic roles. Result(s): In group 1, 6 (25%) of 24 IHH/KS patients had a heterozygous mutation in a second gene, and in group 2, 13 (54.2%) of 24 had a mutation in at least one gene, but none had digenic mutations. In group 2, 7 (29.2%) of 24 had a mutation considered sufficient to cause the phenotype. Conclusion(s): When the 13 most common IHH/KS genes are studied, the overall prevalence of digenic gene mutations in IHH/KS was 12.5%. In addition, approximately 30% of patients without a known mutation had a mutation in a single gene. With the current state of knowledge, these findings suggest that most IHH/KS patients have a monogenic etiology.
KW - Digenic mutations
KW - Kallmann syndrome
KW - idiopathic hypogonadotropic hypogonadism
UR - http://www.scopus.com/inward/record.url?scp=82455162354&partnerID=8YFLogxK
U2 - 10.1016/j.fertnstert.2011.09.046
DO - 10.1016/j.fertnstert.2011.09.046
M3 - Article
AN - SCOPUS:82455162354
SN - 0015-0282
VL - 96
SP - 1424-1430.e6
JO - Fertility and Sterility
JF - Fertility and Sterility
IS - 6
ER -