Table 3.

Thirty-Four Known Genomic Disorders Identified in 522 RHD Cases

Chromosomal Region	CNV Type	Start (Mb)	End (Mb)	Size (Mb)	Syndrome	Discovery (n = 192)	Replication 1 (n = 196)	Replication 2 (n = 134)	Combined (n = 522)	Controls (n = 13,839)	p Value	Prior Association with RHD/Neuropsychiatric Traits?
1p36	dup	2.91	3.65	0.74	1p36 dup	0	0	2	2	0	1.32 × 10−3	N/Y
1p22	dup	89.50	89.97	0.47	1p22.2-p31.1 dupa	0	1	1	2	0	1.32 × 10−3	N/Y
1q21	del	144.11	144.63	0.52	1q21 TAR delb	1	0	0	1	1	0.071	Y/Y
1q21	del	144.80	145.86	1.06	1q21 distal delb	1	3	0	4	4	1.07 × 10−4	Y/N
1q43-q44	del	240.61	245.67	5.06	1q43-q44 del	1	0	0	1	0	0.036	Y/Y
2q37	dup	240.99	242.44	1.45	2q37 dupc	0	1	0	1	0	0.036	Y/Y
3p26	dup	1.35	2.18	0.83	3pter-p25 del	2	0	0	2	8	0.049	N/Y
4p16	del	0.06	17.29	17.23	Wolf-Hirschhornd	0	1	1	2	0	1.32 × 10−3	Y/Y
5p15	dup	0.11	10.96	10.85	5p distal dupd	0	0	1	1	0	0.036	Y/Y
5q14-q23	del	91.46	114.55	23.09	5q interstitial del	0	0	1	1	0	0.036	N/Y
6q13-q14	dup	70.29	70.76	0.47	6q13-q14 del	1	0	0	1	0	0.036	Y/Y
7p22	dup	6.82	7.27	0.45	7p interstitial dup	0	0	1	1	0	0.036	Y/Y
7p21	dup	16.80	17.71	0.91	7p interstitial dup	0	0	1	1	1	0.071	Y/Y
7p15	del	23.68	27.43	3.75	7p15.1-p21.1 del	0	1	0	1	0	0.036	Y/N
7q34-q36	del	141.53	158.81	17.28	7q36 del	1	0	1	2	0	1.32 × 10−3	Y/Y
8p23	dup	8.13	11.94	3.81	8p23.1 dup	1	0	0	1	1	0.071	Y/Y
9p22e	del	14.81	14.97	0.17	9p22.3 del	0	1	0	1	0	0.036	N/N
16p13	dup	0.04	15.09	15.04	16p subtelomeric dupf	0	1	0	1	0	0.036	Y/Y
16p13	dup	15.03	15.80	0.77	16p13.11 dup	1	0	0	1	5	0.199	N/Y
16p11	del	29.55	31.86	2.31	16p11.2 distal del	0	2	0	2	0	1.32 × 10−3	Y/Y
16p11	dup	29.50	30.05	0.55	16p11.2 distal dup	0	0	1	1	3	0.138	N/Y
17p11-p12	dup	16.41	20.23	3.82	Potocki-Lupski syndrome	1	0	1	2	0	1.32 × 10−3	Y/Y
17q11-q12	del	31.89	33.35	1.46	renal cysts and diabetes (HNF1B)g	5	5	1	11	0	1.32 × 10−16	Y/Y
17q11-q12	dup	31.89	33.25	1.36	17q12 dup (HNF1B)	1	0	0	1	1	0.071	Y/Y
17q21	del	40.94	41.41	0.47	17q21.31 del	1	0	0	1	2	0.105	Y/Y
20p11-p13	dup	0.11	24.77	24.66	20p partial trisomya	0	1	0	1	0	0.036	Y/Y
21q22	del	40.51	46.91	6.40	21q partial monosomy	0	0	1	1	0	0.036	N/Y
22q11	dup	15.29	18.61	3.32	22q11.2 dup (VCFS region)c	0	1	0	1	0	0.036	Y/Y
22q11	del	17.27	19.79	2.52	DiGeorge/VCFS del	3	1	0	4	0	1.73 × 10−6	Y/Y
22q13	del	42.94	49.52	6.58	Phelan-McDermid syndromef,g	0	1	1	2	0	1.32 × 10−3	Y/Y
X	gain	XXY	XXY	-	Klinefelter syndrome	1	0	0	1	0	0.044	Y/Y
Xp22	del	6.46	8.10	1.64	Xp22.31 del	2	0	0	2	0	1.92 × 10−3	Y/Y
Xp22	dup	8.19	8.67	0.48	Kallman syndrome region (KAL1)	2	1	0	3	4	1.5 × 10−3	Y/Y
Xq27	dup	139.36	139.91	0.55	mental retardation with panhypopituitarism syndrome	1	0	0	1	0	0.044	N/Y
Total number of known pathogenic CNVs						26	21	14	61	30	9.9 × 10−66	-
Total number of individuals with at least one pathogenic CNV						25 (13%)	18 (9.2%)	12 (9%)	55 (10.5%)	30 (0.21%)	1.22 × 10−58	-

CNV start and end positions are based on UCSC genome build hg18. The symbol for the causal gene at each locus is indicated when known. Fisher’s exact p values for comparison of CNV frequency between combined cohorts (n = 522) and controls (n = 13,839) are indicated. The last row compares the total number of individuals carrying at least one of the CNVs listed in this table (Fisher’s exact test). The following abbreviations are used: CNV, copy-number variation; RHD, renal hypodysplasia; dup, duplication; del, deletion; N, no; Y, yes; and VCFS, velocardiofacial syndrome.

^a–d,f,gSix individuals, corresponding to letters a–d, f, and g, were each diagnosed with two of these syndromes (e.g. “a” indicates that one individual had a 1p22.2-p31.1 deletion and 20p partial trisomy). Additional information and references are reported in Table S8.

^eHomozygous FREM1 mutations within this locus produce bifid nose with or without anorectal and renal anomalies (BNAR [MIM 608980]), but heterozygous mutations are only associated with isolated craniosynostosis (Vissers et al. in Table S8).