Table 1.

Assessment of the 25 IGD Genes Based on the MacArthur Criteria

Gene	Criterion 1: Gene Disruption	Criterion 2: Expression	Criterion 3: Biochemical Function	Criterion 4: Protein Interactions	Criterion 5: Model Systems	Criterion 6: Rescue	Criterion 7: Gene Burden	Number of Criteria Met
KAL1	+	+	+	The first gene discovered	+	+		6
GNRHR	+	+	+	+	+	+		6
GNRH1	+	+	+	+	+	+		6
KISS1	+	+	+	+	+	+		6
FGFR1	+	+	+	+	+			5
FGF8	+	+	+	+	+			5
KISS1R	+	+	+	+	+			5
TAC3	+	+	+	+	+			5
TACR3	+	+	+	+	+			5
PROKR2	+	+	+		+		+	5
PROK2	+	+	+		+		+	5
SEMA3A	+	+	+	+	+			5
SOX10	+	+	+	+	+			5
AXL	+	+	+	+	+			5
SEMA3E	+	+	+	+	+			5
NSMF (NELF)	+	+	+		+			4
WDR11	+	+		+	+			4
CHD7	+	+	+		+			4
FGF17	+	+	+	+				4
IL17RD	+	+	+	+				4
HS6ST1	+	+		+	+			4
FEZF1	+	+	+		+			4
SPRY4	+	+		+				3
FLRT3	+	+		+				3
DUSP6	+	+		+				3

The 25 IGD genes were assessed for the next criteria. Gene disruption: the gene and/or gene product function is demonstrably altered in patients carrying candidate mutations. Expression: the gene is expressed in tissues relevant to the disease of interest and/or is altered in expression in patients who have the disease. Biochemical function: the gene product performs a biochemical function shared with other known genes in the disease of interest, or consistent with the phenotype. Protein interactions: the gene product interacts with proteins previously implicated (genetically or biochemically) in the disease of interest. Model systems: nonhuman animal or cell-culture models with a similarly disrupted copy of the affected gene show a phenotype consistent with human disease state. Rescue: the cellular phenotype in patient-derived cells or engineered equivalents can be rescued by addition of the wild-type gene product. Gene burden: the affected gene shows statistical excess of rare (or de novo) probably damaging variants segregating in cases compared with control cohorts or null models.