Clinical Genetic Testing for Patients With Autism Spectrum Disorders

Yiping Shen; Kira A. Dies; Ingrid A. Holm; Carolyn Bridgemohan; Magdi M. Sobeih; Elizabeth B. Caronna; Karen J. Miller; Jean A. Frazier; Iris Silverstein; Jonathan Picker; Laura Weissman; Peter Raffalli; Shafali Jeste; Laurie A. Demmer; Heather K. Peters; Stephanie J. Brewster; Sara J. Kowalczyk; Beth Rosen-Sheidley; Caroline McGowan; Andrew W. Duda; Sharyn A. Lincoln; Kathryn R. Lowe; Alison Schonwald; Michael Robbins; Fuki Hisama; Robert Wolff; Ronald Becker; Ramzi Nasir; David K. Urion; Jeff M. Milunsky; Leonard Rappaport; James F. Gusella; Christopher A. Walsh; Bai-Lin Wu; David T. Miller; on behalf of the Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration

doi:10.1542/peds.2009-1684

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TABLE 1

Characteristics of Patients in the AC and CHB Cohorts

	AC	CHB	Combined
Patients, n	461	472	933
Age range, y/mo (at visit)	1/7 to 21/10	1/3 to 22/0	–
Gender, n
Male	369	386	755
Female	92	86	178
Diagnosis, n
Autistic disorder	211	236	447
PDD-NOS	227	227	454
Asperger disorder	22	9	31
CDD	1	0	1
Secondary diagnosis, n
MR	54	NA	NA
Seizures	36	NA	NA
Multiple congenital anomalies	16	NA	NA

CHB indicates Children's Hospital Boston; NA, not available; CDD, childhood disintegrative disorder.

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TABLE 2

Karyotype Results

Study ID	Age at Diagnosis, y/mo	Gender	Karyotype	Parental Karyotype	CMA
ASD-09-001	2/5	M	46,XY,t(5;16)(p13.2;p13.2)	ND	Normal
ASD-09-002	3/0	F	46,XX,inv(2)(p11;2q13)	Maternal	Normal
ASD-09-003	2/5	M	46,XY,t(5;17)(q33;p13)	ND	Normal
ASD-09-004	2/6	M	46,XY,t(3;6)(q26.2;q16.2)	Paternal	Normal
ASD-09-005	11/2	M	46,XY,t(3;5)(q26.2;q22)	De novo	Normal
ASD-09-006	1/7	M	46,XX,t(6;7)(q13;q11.2)	De novo	Normal
ASD-09-007	2/11	M	46,XY,t(6;9)(q16.2;q13)	De novo	Normal
ASD-09-008	5/0	M	Duplication (13)(q14.1q21.3)	ND	ND
ASD-09-009	4/0	F	47,XX,+mar.ish der(13) or der(21) (D13Z1/D21Z1+) [4]/46,XX [17]	ND	Normal
ASD-09-010	3	M	46,XY,del (6)(q16.1q21)	ND	16.4 Mb del 6q16.1-q21
ASD-09-011	2/6	M	46,XY,dup(15)(q11q13)	ND	730 kb dup 16q22.1
ASD-09-012	3/8	M	46,XY,del(10)(q26.3).ish del(10) (q telomere)(D10S2490−)	De novo	4.1 Mb del 10q23
ASD-09-013	2/11	M	47,XY,+idic(15)(q13)	ND	11.9 Mb dup 15q11q13.3
ASD-09-014	2/8	F	47,XX,+21	De novo	47,XX,+21
ASD-09-015	5/4	M	47,XY,+21	De novo	47,XY,+21
ASD-09-016	10	M	46,XY,?ins(6)(?p23?q13?q21)	De novo	3.3 Mb del 18p11.31-p11.23; 313 kb del 6q16.3
ASD-09-017	3	M	46,XY,inv(9)(p11q13)	Unknown	Normal
ASD-09-018	3/4	M	46,XY,inv(9)(p11q13)	Unknown	Normal
ASD-09-019	2/10	M	47,XXY	De novo	X Chromosome duplication

M indicates male; t, translocation (involved chromosomes in parentheses); F, female; inv, inversion of chromosome region; ND, not done; de novo, not observed in blood sample from either parent; mar, marker chromosome; ish, in situ hybridization; del, deletion of chromosomal material; dup, duplication of chromosomal material; idic, isodicentric chromosome; ins, insertion of chromosome material.

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TABLE 3

Fragile X Testing Results

Study ID	FMR1 Test Result	Age, y/mo	Gender	CGG Repeat No.	Methylation	Parent of Origin	Karyotype Result	CMA Result
ASD-09-020	Female premutation	2/6	F	69; 32	Normal	Paternal	XX,46	1.6 Mb maternal duplication at Xp22.31
ASD-09-021	Female premutation	2/0	F	56; 46	Normal	Unknown	XX,46	Normal
ASD-09-022	Male full mutation	2/6	M	200	Abnormal	Maternal	XY,46	Normal
ASD-09-023	Female mosaic for full mutation and premutation	5/1	F	>200; 59	Abnormal	Unknown	XX,46	Normal

Normal alleles: ∼5 to 40 repeats; intermediate alleles (also termed “gray zone”): ∼41 to 58 repeats; premutation alleles: ∼59 to 200 repeats; full mutation alleles: >200 repeats; methylation of the FMR1 promoter region typically occurs in full mutation alleles, resulting in silencing of gene expression.

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TABLE 4

Abnormal Chromosomal Microarray Results

Study ID	Chromosome Location	Deletion/Duplication	Size, kb	Chromosome Coordinates	Parent of Origin	Diagnosis	Gender	Karyotype	Fragile X
ASD-09-024	1p36.13	Duplication	16386	762978–17148920	ND	Autistic disorder	M	Normal	Normal
ASD-09-025	1q21.1	Deletion	400	147290000–147700000	De novo	PDD-NOS	M	Normal	Normal
ASD-09-026	1q21.1	Deletion	298	144154012–144451954	Paternal	Autistic disorder	M	Normal	Normal
ASD-09-027	1q43q44	Duplication	3000	239338812–242339608	Maternal	PDD-NOS	F	Normal	Normal
ASD-09-028	2p16.3	Deletion	109	51236317–51344921	De novo	Autistic disorder	M	Normal	Normal
ASD-09-029	2p16.3	Deletion	139	50714297–50853329	ND	PDD-NOS	M	Normal	Normal
ASD-09-030	2p16.3	Deletion	122	51090504–51212385	Paternal	Autistic disorder	M	Normal	Normal
ASD-09-031	2p21	Deletion	112	47460399–47572748	ND	Autistic disorder	F	ND	ND
ASD-09-032	2q13	Deletion	1700	111108666–112819065	ND	Autistic disorder	M	ND	ND
ASD-09-033	2q13	Deletion	298	110050724–110348639	ND	PDD-NOS	M	Normal	Normal
ASD-09-034	2q33.1	Deletion	542	198603505–199146109	De novo	Autistic disorder	M	Normal	Normal
ASD-09-035	3p22.1	Deletion	4317	43443229–47760421	De novo	Autistic disorder	F	Normal	Normal
ASD-09-036	3q23	Deletion	352	143605199–143957178	ND	Autistic disorder	F	Normal	Normal
ASD-09-037	3q29	Duplication	453	198370256–198823726	ND	Autistic disorder	M	ND	Normal
ASD-09-038	4q23	Deletion	1348	100611813–101959551	De novo	Autistic disorder	M	Normal	Normal
ASD-09-039	4q35.2	Deletion	1120	185535833–186654005	ND	Autistic disorder	M	Normal	Normal
ASD-09-040	6p21.32	Duplication	550	31802268–32352051	De novo	Autistic disorder	M	Normal	Normal
ASD-09-041	6q16.1q21	Deletion	16417	94102643–110520288	De novo	Autistic disorder	M	46,XY,del (6) (q16.1q21)	Normal
ASD-09-042	6q16.3	Deletion	312	101812515–102124648	De novo	Autistic disorder	M	46,XY,?ins(6) (?p23?q13?q21)	ND
ASD-09-043	7q11.22	Deletion	43	69475350–69519211	ND	PDD-NOS	M	Normal	Normal
ASD-09-044	7q11.23	Duplication	1817	71 949 830–73 767 523	De novo	Autistic disorder	F	Normal	ND
ASD-09-045	8pq	Mosaic duplication	Entire chr 8	Entire chr 8	De novo	PDD-NOS	M	Abnormal	Normal
ASD-09-046	8q23.3	Deletion	229	114185479–114414476	ND	PDD-NOS	M	Normal	ND
ASD-09-047	8q24.22q24.3	Deletion	5000	136429381–141456935	Maternal	Autistic disorder	F	Normal	Normal
ASD-09-048	9q34.2	Duplication	285	136013220–136298049	De novo	PDD-NOS	M	Normal	Normal
ASD-09-049	10q11.21q11.23	Duplication	5950	45520815–41468963	Maternal	PDD-NOS	M	Normal	Normal
ASD-09-050	10q26.3	Deletion	4100	131300000–135400000	De novo	PDD-NOS	M	46,XY,del(10)(q26.3). ish del(10)(q telomere) (D10S2490-)	Normal
ASD-09-051	12p11.22	Deletion	211	28364520–28575366	De novo	PDD-NOS	F	Normal	Normal
ASD-09-052	12p13.33	Deletion	31	1821094–1852794	ND	PDD-NOS	F	ND	ND
ASD-09-053	12q14.2	Duplication	993	61814661–62807656	Paternal	Autistic disorder	M	Normal	Normal
ASD-09-054	13q12.11	Deletion	304	19698883–20002569	ND	Autistic disorder	M	Normal	Normal
ASD-09-055	13q12.11	Deletion	311	19691189–19860032	ND	Autistic disorder	F	Normal	Normal
ASD-09-056	15q11.1	Duplication	11870	18362555–30232544	ND	Autistic disorder	M	47,XY +idic(15)(q13) unknown parental	Normal
ASD-09-057	15q11.2	Deletion	222	20412298–20634262	Paternal	Autistic disorder	M	Normal	Normal
ASD-09-058	15q11.2	Duplication	277	20428073–20704897	De novo	PDD-NOS	M	Normal	Normal
ASD-09-059	15q11.2q13.1	Duplication	4900	21219452–26214052	Maternal	Autistic disorder	M	ND	Normal
ASD-09-060	15q13.2q13.3	Deletion	1687	28719136–30405675	Maternal	PDD-NOS	M	Normal	Normal
ASD-09-061	15q13.2q13.3	Duplication	1982	28719136–30701432	De novo	Autistic disorder	M	Normal	Normal
ASD-09-062	15q13.2q13.3	Duplication	1982	28719136–30701432	De novo	Autistic disorder	M	Normal	Normal
ASD-09-063	15q13.2q13.3	Deletion	1500	28719136–30298155	ND	PDD-NOS	F	Normal	Normal
ASD-09-064	15q14	Deletion	152	31861894–32014683	ND	Autistic disorder	M	ND	Normal
ASD-09-065	16p11.2	Deletion	220	28732295–28952277	De novo	Autistic disorder	M	Normal	Normal
ASD-09-066	16p11.2	Deletion	546	29560500–30106852	De novo	Autistic disorder	M	Normal	Normal
ASD-09-067	16p11.2	Deletion	546	29560550–30106852	De novo	PDD-NOS	F	Normal	Normal
ASD-09-068	16p11.2	Deletion	546	29560500–30106101	De novo	PDD-NOS	M	Normal	Normal
ASD-09-069	16p11.2	Deletion	546	29560500–30106101	De novo	PDD-NOS	M	Normal	Normal
ASD-09-070	16p11.2	Duplication	679	29560500–30240082	Maternal	PDD-NOS	M	ND	ND
ASD-09-071	16p13.2	Duplication	368	6694662–7062616	ND	PDD-NOS	M	Normal	Normal
ASD-09-072	16q23.3	Deletion	166	81412569–81578850	Maternal	Autistic disorder	M	Normal	Normal
ASD-09-073	7q12	Deletion	1400	31889297–33323031	De novo	PDD-NOS	M	Normal	Normal
ASD-09-042	18p11.31p11.23	Deletion	3300	3905938–7234642	De novo	Autistic disorder	M	46,XY,?ins(6) (?p23?q13?q21)	ND
ASD-09-073	119p13.13	Duplication	168	13378448–13546189	De novo	PDD-NOS	M	Normal	Normal
ASD-09-075	21q	Duplication	Entire chr 21	Entire chr 21	De novo	Autistic disorder	F	47,XX, +21
ASD-09-076	21q	Duplication	Entire chr 21	Entire chr 21	De novo	Autistic disorder	M	47,XY, +21	Normal
ASD-09-077	Xp22.31	Deletion	1628	6463313–8091810	Maternal	Autistic disorder	M	Normal	Normal
ASD-09-078	Xp22.31	Duplication	1624	6492092–8116174	ND	PDD-NOS	F	Normal	ABNORMAL_FEMALE paternal 69 premutation, maternal 32
ASD-09-079	Xq12	Deletion	24	65729442–65753605	Maternal	Autistic disorder	M	Normal	Normal
ASD-09-080	Xq27.1	Deletion	706	138429944–139136376	ND	PDD-NOS	M	Normal	Normal
ASD-09-081	XXY	Duplication	Entire chr X	Entire chr X	De novo	PDD-NOS	M	47,XXY	Normal
ASD-09-082	XYY	Duplication	Entire chr Y	Entire chr Y	De novo	Autistic disorder	M	ND	Normal

Chr indicates chromosome (coordinates reflect human genome build 18 from March 2006); ND, not done; M, male; de novo, not observed in blood sample from either parent; F, female; del, deletion of chromosomal material; ins, insertion of chromosome material; ish, in situ hybridization; idic, isodicentric chromosome.

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TABLE 5

Summary of Genetic Testing in ASD

Test	Abnormal Results
Fragile X DNA, n/N (%)	2/852 (0.23)
G-banded karyotype, n/N (%)	19/852 (2.2)
Chromosomal microarray, n/N (%)
Variant (s) identified	204/848 (24.1)
Clinically significant	59/848 (7.0)
Deletions, n/N (% of abnormal results)	37/59 (62.7)
De novo, n (% of deletions)	16 (43.2)
Maternally inherited	5 (13.5)
Paternally inherited	2 (5.4)
Unknown	15 (40.5)
Duplications, n/N (% of abnormal results)	22/59 (37.3)
De novo, n (% of abnormal duplications)	12 (54.5)
Maternally inherited	4 (18.1)
Paternally inherited	1 (4.5)
Unknown	5 (22.7)