Using Extended Pedigrees to Identify Novel Autism Spectrum Disorder (ASD)
Candidate Genes
Marc Woodbury-Smith1,2, Andrew D. Paterson2,6, Bhooma Thiruvahindrapduram2, Anath
C. Lionel2, Christian R. Marshall2, Daniele Merico2, , Bridget A. Fernandez3, Eric Duku1,
Irene O’Conner1, Christina Chrysler1, Ann Thompson1, Kristiina Tammimies2, Susan
Walker2, Ryan K. C. Yuen2, Mohammed Uddin2, Jennifer L Howe2, Morgan Parlier5,
Kathy Whitten3, Peter Szatmari7, Veronica J. Vieland4,, Joseph Piven5, & Stephen W.
Scherer2.
Supplementary information
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Supplementary Figure 1: Population stratification analysis
0.06
Population
eigenvector2
ASD
CEU
0.04
CHB
CHD
COGEND
0.02
KORA
YRI
0.00
−0.05
−0.04
−0.03
−0.02
−0.01
0.00
0.01
eigenvector1
Key: ASD=autism spectrum disorder; CEU=Northern/Western European in Utah;
CHB=Han Chinese in Beijing, China; CHD= Chinese in Metropolitan Denver;
COGEND=COGEND controls; KORA=KORA controls; YRI=Yoruba in Ibadan, Nigeria.
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Supplementary Figure 2: Examples of extended pedigrees
3
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Supplementary Table 1: Clinical Descriptions of Family Segregating CNV at 11q13.3
Clinical Details
Family
Diagnosisa
l-2
Bipolar Disorder,
(male)
suspected Asperger
disorder
ll-2
Depression
(female)
ll-3
(female)
Bipolar Disorder
ll-5
(male)
Non-ASD, Non-BAP
lll-1
(female)
Anxiety
lll-2
(male)
ASD: Autism-high
functioning
ADI-R=Autism
ADOS M4=Autism
IQb
-
-
WAIS-lll: FSIQ=117
(93rd % ile; HA ),
VIQ=111 (92nd %
ile; HA ),
PIQ=121(90th %
ile; S)
Languagec
Adaptive Behaviorc
Other
-
-
-
CELF 4 Core Language: 121 (92nd
%ile)
Expressive Language: 118 (88th
%ile)
CTOPP: PA: 112 (79th %ile); PM:
130 (98 th %ile; RN: 100 (50th %ile)
CELF 4 Core Language: 120 (91st
%ile)
Expressive Language: 114 (82nd
%ile)
CTOPP: PA: 112 (79th %ile); PM:
115 (84 th %ile; RN: 91 (27th %ile)
CELF 4 Core Language: 120 (91st
%ile)
Expressive Language: 114 (82nd
%ile)
CTOPP: PA: 109 (73rd %ile); PM:
106 (65 th %ile; RN: 100 (50th %ile)
CELF 4 Core Language: 120 (91st
%ile)
Expressive Language: 116 (86th
%ile)
CTOPP: PA: 106 (65th %ile); PM:
121 (92nd %ile); RN: 82 (12th %ile)
CELF 4 Core Language: 121 (92nd
%ile) Expressive Language: 120
(91st %ile) Single words: 36 mo.;
Phrases: 39 mo.
-
Adult EYES:
23/36
-
Adult EYES:
34/36
Adult EYES:
27/36
Adult EYES:
30/36
VABS ABC = 70 (2nd %ile),
COM = 64 (25th %ile), DLS =
81 (10th %ile), and SOC = 73
(4th %ile),
Adult EYES:
28/36
5
lll-3
(male)
ASD: Asperger
Disorder
ADI-R=Autism
ADOS M3=Autism
lll-4
(female)
PDD-NOS
ADI-R=ASD
ADOS M4=Autism
WASI: FSIQ = 121
(92rd % ile; S), VIQ =
140 (99th % ile; VS)
and PIQ = 103
(58th % ile; A)
Leiter-R: brief NVIQ
= 123 (94th % ile; S)
WASI: FSIQ = 80
(9th % ile; LA), VIQ
= 80 (9th % ile; LA)
and PIQ = 85
(16th % ile; LA)
Leiter-R: brief NVIQ
= 73 (4th % ile; B)
CTOPP: PA: 115 (84th %ile); PM:
112 (79 th %ile; RN: 109 (73rd %ile)
CELF 4 Core Language: 124 (95th
%ile) Expressive Language: 120
(91st %ile)
Single words: 15 mo.; Phrases 16
mo.
CTOPP: PA: 91 (27th %ile); PM: 76
(5th %ile; RN: 94 (35th %ile)
CELF 4 Core Language: 91 (27th
%ile) Expressive Language: 93
(32nd %ile)
Single words: 18 mo.; Phrases 30
mo.
VABS ABC = 81 (10th %ile),
COM = 90 (25th %ile), DLS =
79 (8th %ile), and SOC = 80
(9th %ile),
VABS ABC = 65 (1st %ile),
COM = 64 (1st %ile), DLS = 69
(2nd %ile), and SOC = 70 (2nd
%ile),
Adult Eyes:
17/36
Refer to pedigree in Figure 1. The following abbreviations are used: IQ, intelligence quotient; ASD, autism spectrum disorder; % ile, percentile.
aThe autism-spectrum diagnosis is based on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS; one of four possible modules is administered on the basis of age and
language level).
bIQ was measured with an age-appropriate Wechsler scale (WPPSI, Wechsler Preschool and Primary Scale of Intelligence; WISC, Wechsler Intelligence Scale for Children; or WASI, Wechsler Abbreviated Scale of
Intelligence, Wechsler Adult Intelligence Scale-Third Edition or WAIS-lll). Standard scores and percentiles are presented for full-scale IQ (FSIQ), verbal IQ (VIQ), and/or performance IQ (PIQ). FSIQ is not a valid estimate of
IQ when significant discrepancy exists between VIQ and PIQ. Leiter International Performance Scale-Revised (Leiter-R) is a measure of nonverbal IQ (NVIQ) only. Percentile classifications are the following: very superior (VS;
>98th % ile), superior (S; 91st–97th % ile), high average (HA; 75th–90th % ile), average (A; 25th–74th % ile), low average (LA; 9th–24th % ile), borderline (B; 2nd–8th % ile), and extremely low (EL; <2nd % ile).
cLanguage was measured with the Clinical Evaluation of Language Fundamentals, 4th Edition (CELF-4) which is a widely used measure for the direct assessment of linguistic competence including morphology, syntax, and
semantics. Standard scores and percentiles are presented for core language (CL) and expressive language (EL). Out of age range norms were used for individuals older than 21. The Comprehensive Test of Phonological
Processing (CTOPP) is a measure of phonological processing. Standard scores and percentiles are presented for Rapid Naming (RN), Phonological Awareness (PA) and Phonological Memory (PM). Out of age range norms were
used for individuals older than 24.
cAdaptive Behavior was measured with the Vineland Adaptive Behavior Scales (VABS). Standard score and percentiles are presented for adaptive behavior composite (ABC), communication (COM), daily living skills (DLS),
socialization (SOC), and motor (MOT; only for children 7 years old or younger).
The Eyes Test is an advanced social-cognition task in which 36 photographs depicting only the eye region of the face are presented and individual must choose which of 4 complex mental state words describes the feeling of the
person depicted
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Supplementary Figure 3: Gene annotation of 11q13 duplications (See text for details)
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