Table 2a.

Molecular Genetic Testing Used in Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency: Most Common Genetic Causes

Gene 1, 2% of IGD Attributed to Pathogenic Variants in Gene 3Proportion of Pathogenic Variants 4 Identified by Method
Sequence analysis 5Gene-targeted deletion/duplication analysis 6
ANOS1 (KAL1)5%-10% (KS)~88%-99%≤12% in one study (4/33 persons w/KS) 7

CHD7

5%-10% (KS or nIGD)~100%Unknown 8

FGFR1

~10% (KS or nIGD)~99%Rare 9

GNRHR

5%-10% (nIGD)~100%Unknown 8

IL17RD

2%-5% (KS or nIGD)~100%Unknown 8

PROKR2

~5% (KS or nIGD)~100%Unknown8

SOX10

2%-5% (KS)~100%Unknown 8

TACR3

~5% (nIGD)~100%Unknown 8

Pathogenic variants of any one of the genes included in this table account for >2% of IGD.

KS = Kallmann syndrome; nIGD = normosmic isolated gonadotropin-releasing hormone deficiency

1.

Genes are listed in alphabetic order.

2.

See Table A. Genes and Databases for chromosome locus and protein.

3.

Proportion of IGD attributed to these genes is determined from the author's cohort of 950 probands with IGD who were screened for rare sequence variants (<1% of control cohort).

4.

See Molecular Genetics for information on pathogenic allelic variants detected.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

12% of persons with KS had intragenic deletions in ANOS1 [Pedersen-White et al 2008].

8.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

9.

FGFR1 deletions are rare [Trarbach et al 2010b].

From: Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency

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