The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome.
OBJECTIVE
To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS).


METHODS
Molecular analysis of DNA in IHH/KS patients.


METHODS
Academic medical center.


METHODS
Twenty-four IHH/KS patients with a known mutation (group 1) and 24 IHH/KS patients with no known mutation (group 2).


METHODS
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Neuroscience Program, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
Samuel D
SD
Quaynor
Hyung-Goo
HG
Kim
Elizabeth M
EM
Cappello
Tiera
T
Williams
Lynn P
LP
Chorich
David P
DP
Bick
Richard J
RJ
Sherins
Lawrence C
LC
Layman
D000293:Adolescent; D000328:Adult; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007006:Hypogonadism / Q000453:epidemiology / Q000235:genetics*; D017436:Kallmann Syndrome / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008954:Models, Biological; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D055815:Young Adult