1
SUPPLEMENTARY MATERIAL
Delineating the 15q13.3 Microdeletion Phenotype: A Case Series and
Comprehensive Review of the Literature
Supplementary Material
Table S1. Results of literature search for 15q13.3 deletion cases
Page
2-9
Table S2. Full phenotypic details for adult cases with 15q13.3
deletions
See excel attachment
Table S3. Full phenotypic details for child cases with 15q13.3
deletions
See excel attachment
Table S4. Coding key for clinical features listed in Table S2 and
S3
10-20
Table S5. Obstetric and perinatal outcomes related to 27 cases
with 15q13.3 deletions
21-22
Table S6. Control datasets examined for 15q13.3 (BP4-BP5)
deletions
22-23
Table S7. Control dataset acknowledgments
24
2
Table S1. Results of literature search for 15q13.3 deletion cases
Our initial search revealed 55 primary reports containing cases with 15q13.3 deletions.1-55
1.
Banka S, Fitzgibbon GJ, Gaunt L, Rankin WJ, Clayton-Smith J. A novel 800 kb
microduplication of chromosome 16q22.1 resulting in learning disability and
epilepsy may explain phenotypic variability in a family with 15q13 microdeletion.
Am. J. Med. Genet. A. Jun 2011;155A(6):1453-1457.
2.
Shinawi M, Schaaf CP, Bhatt SS, et al. A small recurrent deletion within 15q13.3
is associated with a range of neurodevelopmental phenotypes. Nat. Genet. Dec
2009;41(12):1269-1271.
3.
Spielmann M, Reichelt G, Hertzberg C, et al. Homozygous deletion of
chromosome 15q13.3 including CHRNA7 causes severe mental retardation,
seizures, muscular hypotonia, and the loss of KLF13 and TRPM1 potentially
cause macrocytosis and congenital retinal dysfunction in siblings. European
journal of medical genetics. Jul-Aug 2011;54(4):e441-445.
4.
Cubells JF, Deoreo EH, Harvey PD, et al. Pharmaco-genetically guided treatment
of recurrent rage outbursts in an adult male with 15q13.3 deletion syndrome. Am.
J. Med. Genet. A. Apr 2011;155A(4):805-810.
5.
Endris V, Hackmann K, Neuhann TM, et al. Homozygous loss of CHRNA7 on
chromosome 15q13.3 causes severe encephalopathy with seizures and hypotonia.
Am. J. Med. Genet. A. Nov 2010;152A(11):2908-2911.
6.
Liao J, DeWard SJ, Madan-Khetarpal S, Surti U, Hu J. A small homozygous
microdeletion of 15q13.3 including the CHRNA7 gene in a girl with a spectrum
3
of severe neurodevelopmental features. Am. J. Med. Genet. A. Nov
2011;155A(11):2795-2800.
7.
Lepichon JB, Bittel DC, Graf WD, Yu S. A 15q13.3 homozygous microdeletion
associated with a severe neurodevelopmental disorder suggests putative functions
of the TRPM1, CHRNA7, and other homozygously deleted genes. Am. J. Med.
Genet. A. May 2010;152A(5):1300-1304.
8.
Coppola A, Bagnasco I, Traverso M, et al. Different electroclinical picture of
generalized epilepsy in two families with 15q13.3 microdeletion. Epilepsia. May
2013;54(5):e69-73.
9.
Ben-Shachar S, Lanpher B, German JR, et al. Microdeletion 15q13.3: a locus with
incomplete penetrance for autism, mental retardation, and psychiatric disorders. J.
Med. Genet. Jun 2009;46(6):382-388.
10.
Mikhail FM, Lose EJ, Robin NH, et al. Clinically relevant single gene or
intragenic deletions encompassing critical neurodevelopmental genes in patients
with developmental delay, mental retardation, and/or autism spectrum disorders.
Am. J. Med. Genet. A. Oct 2011;155A(10):2386-2396.
11.
Miller DT, Shen Y, Weiss LA, et al. Microdeletion/duplication at 15q13.2q13.3
among individuals with features of autism and other neuropsychiatric disorders. J.
Med. Genet. Apr 2009;46(4):242-248.
12.
Hoppman-Chaney N, Wain K, Seger P, Superneau D, Hodge J. Identification of
single gene deletions at 15q13.3: further evidence that CHRNA7 causes the
15q13.3 microdeletion syndrome phenotype. Clin. Genet. Apr 2013;83(4):345351.
4
13.
Rosenfeld JA, Stephens LE, Coppinger J, et al. Deletions flanked by breakpoints
3 and 4 on 15q13 may contribute to abnormal phenotypes. Eur. J. Hum. Genet.
May 2011;19(5):547-554.
14.
van Bon BW, Mefford HC, Menten B, et al. Further delineation of the 15q13
microdeletion and duplication syndromes: a clinical spectrum varying from nonpathogenic to a severe outcome. J. Med. Genet. Aug 2009;46(8):511-523.
15.
Masurel-Paulet A, Andrieux J, Callier P, et al. Delineation of 15q13.3
microdeletions. Clin. Genet. Aug 2010;78(2):149-161.
16.
Sharp AJ, Mefford HC, Li K, et al. A recurrent 15q13.3 microdeletion syndrome
associated with mental retardation and seizures. Nat. Genet. Mar 2008;40(3):322328.
17.
Sharp AJ, Hansen S, Selzer RR, et al. Discovery of previously unidentified
genomic disorders from the duplication architecture of the human genome. Nat.
Genet. Sep 2006;38(9):1038-1042.
18.
Mannik K, Parkel S, Palta P, et al. A parallel SNP array study of genomic
aberrations associated with mental retardation in patients and general population
in Estonia. European journal of medical genetics. Mar-Apr 2011;54(2):136-143.
19.
Dibbens LM, Mullen S, Helbig I, et al. Familial and sporadic 15q13.3
microdeletions in idiopathic generalized epilepsy: precedent for disorders with
complex inheritance. Hum. Mol. Genet. Oct 1 2009;18(19):3626-3631.
20.
Galizia EC, Srikantha M, Palmer R, et al. Array comparative genomic
hybridization: results from an adult population with drug-resistant epilepsy and
co-morbidities. European journal of medical genetics. May 2012;55(5):342-348.
5
21.
Heinzen EL, Radtke RA, Urban TJ, et al. Rare deletions at 16p13.11 predispose to
a diverse spectrum of sporadic epilepsy syndromes. Am. J. Hum. Genet. May 14
2010;86(5):707-718.
22.
Helbig I, Mefford HC, Sharp AJ, et al. 15q13.3 microdeletions increase risk of
idiopathic generalized epilepsy. Nat. Genet. Feb 2009;41(2):160-162.
23.
Kevelam SH, Jansen FE, Binsbergen E, et al. Copy number variations in patients
with electrical status epilepticus in sleep. J. Child Neurol. Feb 2012;27(2):178182.
24.
McMahon JM, Scheffer IE, Nicholl JK, et al. Detection of microchromosomal
aberrations in refractory epilepsy: a pilot study. Epileptic disorders : international
epilepsy journal with videotape. Sep 2010;12(3):192-198.
25.
Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in
epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.
PLoS Genet. May 2010;6(5):e1000962.
26.
Muhle H, Mefford HC, Obermeier T, et al. Absence seizures with intellectual
disability as a phenotype of the 15q13.3 microdeletion syndrome. Epilepsia. Dec
2011;52(12):e194-198.
27.
Kirov A, Dimova P, Todorova A, et al. 15q13.3 microdeletions in a prospectively
recruited cohort of patients with idiopathic generalized epilepsy in Bulgaria.
Epilepsy Res. May 2013;104(3):241-245.
28.
de Kovel CG, Trucks H, Helbig I, et al. Recurrent microdeletions at 15q11.2 and
16p13.11 predispose to idiopathic generalized epilepsies. Brain. Jan 2010;133(Pt
1):23-32.
6
29.
Guilmatre A, Dubourg C, Mosca AL, et al. Recurrent rearrangements in synaptic
and neurodevelopmental genes and shared biologic pathways in schizophrenia,
autism, and mental retardation. Arch. Gen. Psychiatry. Sep 2009;66(9):947-956.
30.
Pagnamenta AT, Wing K, Sadighi Akha E, et al. A 15q13.3 microdeletion
segregating with autism. Eur. J. Hum. Genet. May 2009;17(5):687-692.
31.
Pinto D, Pagnamenta AT, Klei L, et al. Functional impact of global rare copy
number variation in autism spectrum disorders. Nature. Jul 15
2010;466(7304):368-372.
32.
Shen Y, Dies KA, Holm IA, et al. Clinical genetic testing for patients with autism
spectrum disorders. Pediatrics. Apr 2010;125(4):e727-735.
33.
Girirajan S, Brkanac Z, Coe BP, et al. Relative burden of large CNVs on a range
of neurodevelopmental phenotypes. PLoS Genet. Nov 2011;7(11):e1002334.
34.
International Schizophrenia Consortium. Rare chromosomal deletions and
duplications increase risk of schizophrenia. Nature. Sep 11 2008;455(7210):237241.
35.
Levinson DF, Duan J, Oh S, et al. Copy number variants in schizophrenia:
confirmation of five previous findings and new evidence for 3q29 microdeletions
and VIPR2 duplications. Am. J. Psychiatry. Feb 1 2011;168(3):302-316.
36.
Stefansson H, Rujescu D, Cichon S, et al. Large recurrent microdeletions
associated with schizophrenia. Nature. Sep 2008;455(7210):232-236.
37.
Van Den Bossche MJ, Johnstone M, Strazisar M, et al. Rare copy number variants
in neuropsychiatric disorders: Specific phenotype or not? American journal of
7
medical genetics. Part B, Neuropsychiatric genetics : the official publication of
the International Society of Psychiatric Genetics. Oct 2012;159B(7):812-822.
38.
Cooper GM, Coe BP, Girirajan S, et al. A copy number variation morbidity map
of developmental delay. Nat. Genet. Sep 2011;43(9):838-846.
39.
Girirajan S, Rosenfeld JA, Coe BP, et al. Phenotypic heterogeneity of genomic
disorders and rare copy-number variants. N. Engl. J. Med. Oct 4
2012;367(14):1321-1331.
40.
Girirajan S, Dennis MY, Baker C, et al. Refinement and discovery of new
hotspots of copy-number variation associated with autism spectrum disorder. Am.
J. Hum. Genet. Feb 7 2013;92(2):221-237.
41.
Glessner JT, Reilly MP, Kim CE, et al. Strong synaptic transmission impact by
copy number variations in schizophrenia. Proc. Natl. Acad. Sci. U. S. A. Jun
2010;107(23):10584-10589.
42.
Guha S, Rees E, Darvasi A, et al. Implication of a rare deletion at distal 16p11.2
in schizophrenia. JAMA psychiatry. Mar 2013;70(3):253-260.
43.
Kirov G, Pocklington AJ, Holmans P, et al. De novo CNV analysis implicates
specific abnormalities of postsynaptic signalling complexes in the pathogenesis of
schizophrenia. Mol. Psychiatry. Feb 2012;17(2):142-153.
44.
Sahoo T, Theisen A, Rosenfeld JA, et al. Copy number variants of schizophrenia
susceptibility loci are associated with a spectrum of speech and developmental
delays and behavior problems. Genetics in Medicine. Oct 2011;13(10):868-880.
8
45.
Sanders SJ, Ercan-Sencicek AG, Hus V, et al. Multiple recurrent de novo CNVs,
including duplications of the 7q11.23 Williams syndrome region, are strongly
associated with autism. Neuron. 2011;70:863-885.
46.
Williams NM, Zaharieva I, Martin A, et al. Rare chromosomal deletions and
duplications in attention-deficit hyperactivity disorder: a genome-wide analysis.
Lancet. Oct 2010;376(9750):1401-1408.
47.
Bergen SE, O'Dushlaine CT, Ripke S, et al. Genome-wide association study in a
Swedish population yields support for greater CNV and MHC involvement in
schizophrenia compared with bipolar disorder. Mol. Psychiatry. Sep
2012;17(9):880-886.
48.
Buizer-Voskamp JE, Muntjewerff JW, Strengman E, et al. Genome-wide analysis
shows increased frequency of copy number variation deletions in Dutch
schizophrenia patients. Biol. Psychiatry. Oct 1 2011;70(7):655-662.
49.
Hehir-Kwa JY, Rodriguez-Santiago B, Vissers LE, et al. De novo copy number
variants associated with intellectual disability have a paternal origin and age bias.
J. Med. Genet. Nov 2011;48(11):776-778.
50.
Kaminsky EB, Kaul V, Paschall J, et al. An evidence-based approach to establish
the functional and clinical significance of copy number variants in intellectual and
developmental disabilities. Genetics in medicine : official journal of the American
College of Medical Genetics. Sep 2011;13(9):777-784.
51.
Langley K, Martin J, Agha SS, et al. Clinical and cognitive characteristics of
children with attention-deficit hyperactivity disorder, with and without copy
number variants. Br. J. Psychiatry. Nov 2011;199(5):398-403.
9
52.
Nicholl J, Waters W, Suwalski S, et al. Epilepsy with cognitive deficit and autism
spectrum disorders: prospective diagnosis by array CGH. American journal of
medical genetics. Part B, Neuropsychiatric genetics : the official publication of
the International Society of Psychiatric Genetics. Jan 2013;162(1):24-35.
53.
Stewart LR, Hall AL, Kang SH, Shaw CA, Beaudet AL. High frequency of
known copy number abnormalities and maternal duplication 15q11-q13 in
patients with combined schizophrenia and epilepsy. BMC Med Genet.
2011;12:154.
54.
Vacic V, McCarthy S, Malhotra D, et al. Duplications of the neuropeptide
receptor gene VIPR2 confer significant risk for schizophrenia. Nature. Mar 24
2011;471(7339):499-503.
55.
Williams NM, Franke B, Mick E, et al. Genome-wide analysis of copy number
variants in attention deficit hyperactivity disorder: the role of rare variants and
duplications at 15q13.3. Am. J. Psychiatry. Feb 2012;169(2):195-204.
10
Table S4. Coding key for clinical features listed in Table S2 and S3
ID
0
1
2
3
4
5
6
7
8
DD
1
2
3
4
5
6
7
8
9
10
11
MR, severity unspecified
Severe
Moderate
Mild
Normal
Learning
Difficulties/Disabilities
Cognitive Deficits
Dyslexia
Borderline intellect
Dev. Delay, severity
unspecified
Moderate Delay
Language delay
Motor Delay
Cognitive Delay
Motor and Language Delay
Language and Cognitive
Delay
Normal
Severe Delay
No motor delay
Mild Delay
Seizure
1
Seizure, unspecified
2
Absence/tonic clonic
3
Grand Mal
4
Absence
5
Generalized Tonic-Clonic
Seizure
7
None
8
Absence/Myoclonus
9
Myoclonus
10
Absence/Generalized TonicClonic Seizure
11
Absence/GTCS/Myoclonus
12
Myoclonus/GTCS
14
Absence and
11
15
16
pharmacoresistant
Febrile Seizure
Hyperthermic seizure
Epilepsy
1
Myoclonic
2
Intractable
3
No
4
Juvenile Absence
epilepsy/juvenile myoclonic
epilepsy
5
Juvenile Absence epilepsy
6
Juvenile Myoclonic epilepsy
7
Idiopathic Epilepsy
8
Epilepsy, type unspecified
10
Absence Epilepsy
11
Generalized Epilepsy
12
Pharmacoresistant TonicClonic
13
Idiopathic Absence Epilepsy
14
Refractory childhood
absence epilepsy
15
Tonic clonic
16
Primary generalized epilepsy
17
Landau Kleffner syndrome
EEG
1
2
Abnormal
Normal
Autism
1
Autism
2
ASD
3
Normal
4
Asperger’s Syndrome
5
PDD-NOS
6
ASD features
PDD
1
PDD present
SZ
1
Schizophrenia
2
Normal
Family Hx
12
1
2
Present
Absent
Bipolar disorder
1
Bipolar disorder present
Mood Disorder
1
Mood disorder, unspecified
2
Depression
3
Anxiety
4
Normal
5
Oppositional defiant disorder
ADHD
1
ADHD present
Behaviour
1
Behaviour Problem
2
Normal
3
Obsessive, easily upset,
sensitive to sounds
5
Hyperkinetic
6
Externalizing problems,
withdrawal
8
Encopresis
9
Inhibition
10
Self-mutilation/ Injurious
11
Hyperphagia
12
Obsessive, limited social
communication
14
Temper tantrums
15
Impulsive
16
Aggressive/Rage
17
Irritable
18
Rocking
20
Borderline personality
disorder, narcissistic
21
Hyperactivity
22
Poor concentration
23
Poor attention
Sleeping
1
Sleeping problem
Cardiovascular
13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Mitral Valve Prolapse
TOF
Right cardiac hypoplasia with
tricuspid stenosis
Normal
Aneurysm of the interauricular
septum
Ventricular septal defect
Complex CHD
Abnormal Echo
Normal EKG
Lymphedema
Transient cyanosis
Hypertension
Mild cardiomegaly
Abnormal Echo
MI
CHF
Coronary artery disease
Angina
Normal echo
No heart murmur
Born with hole in heart
Neurology
1
Abnormal Brain MRI
2
Normal Brain MRI
3
Abnormal Neurological Exam
4
Normal Neurological Exam
5
Arachnoid Cyst
6
Vertigo
7
Tremor
8
Head Injury
9
Dyspraxia
11
Hydrocephalus
12
Ataxia
14
Bleed in occipital area
15
Multilevel degenerative disc
disease, spinal stenosis
16
Acrocephaly/turricephaly
17
Normal neurological exam
18
Mild clumsiness
19
Abnormal CT head without
contrast
20
Normal spine
14
21
22
23
24
25
26
27
Choreoathetosis
Lack of coordination
Migraines
Periventricular heterotopia
Poor suck at birth
Feeding difficulties
Stereotypic
Hypotonia
1
Yes
2
No
Failure to thrive
1
Yes
ENT
1
Hearing problem
Medical Condition
1
Subcutaneous vessels
2
Type II diabetes
3
Fecal Incontinence
4
Spina bifida occulta
5
Scoliosis
6
Right pyelic dialation
7
UTI
8
Hypertrichosis
9
Hiatal hernia
10
Enuresis
11
Polycythaemia
12
Respiratory complications
13
Jaundice
14
Hypogammaglobulinemia &
recurrent viral infections
15
Enteritis
16
Iguinal hernia
17
GERD
18
Cryptochridia
19
Constipation
20
Ornithine transcarbamylase
deficiency
21
Neutropenia
22
Mild ileal stenosis
23
Cavernous hemangioma
24
Pectus excavatum
15
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Anemia
Hypercalcemia
Osteoporosis
Hyperprolactinemia
Hyperlipidemia
Hypernatremia
Small bowel obstruction
Duodenal ulcer
Osteoarthritis
Breast CA
Hiatal hernia
No testis
Congenital thyroid hypoplasia
Sleep apnea
Tubal ligation
Gallbladder removal
Hypercholesteroemia
Kidney stones
Pneumonia
Hydronephrosis
Carpel tunnel syndrome
Bowel polyps
Tonsillitis
Arthritis
Asthma
Multiple Sclerosis
Hypothyroidism
Basal cell carcinoma
Syringomyelia
Speech
1
Delay
2
Poor Vocalization
3
Nasal
4
Normal
5
Mildly dysarthric
6
Few Sentences
7
No speech
8
Articulation Problem
9
Echolalia
10
Stuttering
11
Abnormal Resonance
12
Impaired
13
Mildly impaired
14
Moderately impaired
16
15
16
17
18
19
20
21
22
23
24
Limited Speech
Unclear speech
Speech Apraxia
Impaired receptive speech
Normal receptive speech
Impaired expressive speech
Impaired written language
Normal Written language
Speech problem, unspecified
Agrammatism
Eye Pathology
1
Normal
2
Myopia
3
Strabismus
4
Nystagmus
5
Retinal dystrophy
6
Retinal dysfunction
7
Colobomatous
8
Visual Impairment
9
Blepharophismosis
10
Astigmatism
11
Asymmetrical optic nerve
cupping
12
Hyperopic, amblyopic, and
strabismus
Eye Dysmorphology
1
Normal
2
Upslanting palpebral fissures
3
Normal interpupillary space
4
Hypertelorism
5
Synorphris
6
Asymmetric
7
Microexotropia
8
Good eye convergence
9
Iris coloboma, R eye
10
Prognathism
11
Right optic pit, possible
coloboma
12
Epicanthic folds
13
Deep set eyes
14
S shaped upper eyelids
15
Short palpebral fissures
17
16
17
18
19
20
21
Downslanting palpebral
fissures
Ptosis
Long palpebral fissures
Small eyes
Hypotelorism
Bulging eyes
Ear Dysmorphology
1
Normal
2
Posterior rotated
3
Thick helices
4
Low set
5
Large
6
Wide concha
7
Mildly deficient ear lobules
8
Folded helices
9
Protruding
10
Over folded helices
11
Long
12
Antihelix
13
Hypoplasia
14
Prominent
15
Small ears
16
Large ear lobule
17
7 cm, two stabdard deviations
above normal
Nose Dysmorphology
1
Normal
2
Depressed Nasal bridge
3
Anteverted Nares
4
Wide nasal bridge
5
Prominent
6
Bulbous tip
7
Fleshy nose
9
Prominent nasal tip
10
Full nasal tip
11
Pointed columella below the
alea
12
Upward position of nares
13
Short nose with upturned tip
14
Broad nasal root
15
Low nasal bridge
16
Long, tubular nose
18
17
Flat nasal bridge
Philtrum
1
Normal
2
Smooth
3
Short
4
Prominent
5
Thick
6
Flat
Face
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Normal
Round
Long
Full
Flat face
Myopathic
High forehead
Grooved chin
Large forehead
Facial dysmorphism,
unspecified
Prominent chin
Hypoplasia
Triangular face
Triangular chin
Short forehead
Small
Thin
Flat forehead
No facial dysmorphism
No consistent dysmorphic
features
Retrognathia
Lips/Mouth
1
Normal
2
Everted lower lip
3
Full lips
4
Everted upper lip
5
Small mouth
6
Thin upper lip
7
Large mouth
8
Protuberant tongue
9
Narrow palate
19
10
Open mouth
Teeth
1
Normal
2
Widely spaced
3
Malocclusion
4
Small teeth
5
Delayed eruption
6
Multiple fillings and cavities
7
Overcrowded
8
Multiple dental extractions
9
Irregular teeth, especially
upper central incisors
10
Small mandible
11
Excessive fibrotic tissue on
maxillary ridge
12
Teeth removed
13
Malar hypoplasia
Skin
1
2
3
4
5
6
7
8
9
10
11
12
13
Normal
Pigmented naevi
Café au lait
Dry
Many birthmarks
Hyper/Hypopigmented
macules
Single hypopigmented macules
Eczema
Angioma of the forehead and
upper lip
Strawberry hemangioma on
arm
Eczema
Normal skin and vasculature
Hypertrichosis
Lower Extremities
1
Normal
2
Hallux valgus
3
Hypoplastic 4th and 5th toes
4
External rotation of the feet
5
Patellar luxation
6
Broad feet
20
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Brachydactyly
Broad toes
Wide sandal gap
Pes planus
Long toes
Large toes
Short toes
Broad lower legs
Pes cavus
Deep plantar creases
Hammer toes
Toenails removed
Morton’s Neuroma
Syndactyly of the 2-3rd digit
Hands
1
Normal
2
Stiff fingers
3
Short fourth metacarpals
4
Short 5th finger
5
5th finger clinodactyly
6
Tapering fingers
7
Lax thumb joint
8
Short palmar crease
9
Long fingers
10
Deep palmar crease
11
Coarse hands
12
Triphalangeal thumb
13
Bilateral simian creases
14
Broad hands
15
Brachydactyly
16
Fainted terminal creases
17
Prominent finger pads
18
Broad finger tips
19
Digital findings
20
Brachymetacarpy
21
Camptodactyly 4th and 5th
fingers
22
Single palmar crease
23
Broad Hallux
24
Short fourth and 5th
metacarpals
25
Short 5th metacarpals
21
Table S5: Obstetric and perinatal outcomes related to 27 cases with 15q13.3 deletions
Obstetric outcomes for probands with the 15q13.3 microdeletion (n=23)
No. ID
Proband
Sex Ethnicity Inheritance Gestational
age (y)
age (weeks)
Birth weight
(grams)
Birth weight
(percentile)
Pregnancy history
Delivery history
1
Case 231
Child
F
CAU
de novo
37
2510
<3a
Partial placenta previa at 34
weeks, unaffected mother
developed gestational
diabetes
-
2
Case 229
Child
M
NR
Unknown
~32-33
2000
50
Placenta previa, premature,
pregnancy complicated by
asthma, gestational diabetes,
and seizure disorder in
mother with unknown
15q13.3 deletion status
Emergency Cesarean
section
3
Case 5c
14
M
CAU
Maternal
~32
1587
25
Placenta previa, premature
Emergency Cesarean
section
4
Case 21
37
M
CAU
Maternal
Term
NR
NR
Placenta previa, maternal
post-partum hemorrhage
Spontaneous vaginal
5
Case 214
Child
M
CAU
Maternal
NR
NR
NR
Premature rupture of
membranes
Induced vaginal
(deterioration in the fetal
heart rate)
6
Case 241
8
M
NR
Unknown
35
2520
50
Premature rupture of
membranes at 30 weeks,
premature, IUGR
Cesarean section
7
Case 232
9
F
CAU
de novo
Term
2550
<3a
IUGR
-
8
Case 251
1.5
F
NR
Maternal
28
1100
50
Premature
-
9
Case 259
3.6
F
NR
Maternal
34
NR
NR
Premature
-
10
Case 248
14
F
NR
Paternal
42
3500
50
Postmature
-
11
Case 255
13
M
NR
Maternal
42
NR
NR
Postmature
-
12
Case 113
44
M
NR
Maternal
42
3500
50
Postmature
-
22
Obstetric outcomes for fetuses with the 15q13.3 microdeletion (continued)
No. ID
Proband Sex
Ethnicity Inheritance Gestation
age (y)
age (weeks)
Birth weight
(grams)
Birth weight
(percentile)
Pregnancy history
Delivery history
13
Case 258
3.5
F
NR
Maternal
NR
NR
NR
Pregnancy induced due to
malformation of the fetal
heart
-
14
Case 216
Child
M
CAU
Maternal
NR
NR
NR
Uncomplicated
Cesarean section (breech)
15
Case 121
8
F
CAU
Maternal
41
2400
<3a
-
Emergency cesarean
section (fetal distress)
16
Case 228
Child
M
NR
Maternal
NR
NR
NR
-
Cesarean section
17
Case 254
4.75
F
NR
Paternal
40
4400
>97b
Polyhydramnios
-
18
Case 114
28
F
NR
Paternal
Term
4050
90b
-
-
19
Case 191
1.5
F
CAU
Paternal
NR
NR
NR
-
-
20
Case 247
5.5
M
NR
Maternal
37
4170
90b
-
-
21
Case 250
4
M
NR
Maternal
40
4520
>90b
-
-
22
Case 7
39
F
CAU
Unknown
NR
4224
b
-
-
23
Case 257
5
M
NR
Unknown
Term
3150
15-20
Gestational diabetes
-
Obstetric outcomes for transmitting mothers (n=4)
No. ID
Age
Sex
Ethnicity
(y)
24
Case 2
75
F
CAU
Inheritance
Obstetric history (deletion status of the fetus where applicable was unknown)
Unknown
Two spontaneous abortions at age 25 and 26, one male child born at 30 weeks by Cesarean section, and one
male stillbirth with nuchal cord
25
Case 6
39
F
CAU
Unknown
1 spontaneous abortion
26
Case 83
NR
F
CAU
Unknown
7 spontaneous abortions
27
Case 4
56
F
CAU
Maternal
Primary infertility
F; female, M; male. CAU; Caucasian , NR; not reported, -; none known; IUGR; intrauterine growth retardation, , asmall for gestational age, blarge for gestational age, cCase 5 is a
transmitting mother who developed placenta previa while pregnant with her son who carries 15q13.3 deletion (son not included as a case in this study).
23
Table S6. Control datasets examined for 15q13.3 (BP4-BP5) deletions
Control dataset
# individuals
Array type
Description of dataset
# of 15q13.3
(BP4-BP5)
deletions
# of 15q13.3
(BP4-BP5)
duplications
Breakpoints (hg 18)
POPGEN controls
1,123
Affymetrix 6.0
0
1 duplication
chr15:28,700,879-30,299,512
Ottawa Heart Institute
controls
1,234
Affymetrix 6.0
Krawczak et al. 2006
(Community Genet)
Stewart et al. 2009 (J Am
Coll Cardioll)
0
0
HapMap (Phase 3)
controls
Wellcome Trust Case
Control Consortium
(WTCCC) controls
Ontario Population
Genomics Platform
(OPGP) controls
SAGE consortium
controls
Health, Aging, and Body
Composition (Health
ABC) Study controls
Ontario ARCTIC controls
1,056
Affymetrix 6.0
0
0
4,783
Affymetrix 6.0
Altshuler et al. 2010 (Nature
)
Craddock et al. 2010 (Nature)
0
2
416
Affymetrix 6.0
Silversides et al. 2012 (PLoS
Genet)
0
0
1,287
Illumina 1M
Bierut et al. 2010 (PNAS)
0
0
2,566
Illumina 1M-Duo
Coviello et al. 2012 (PLoS
Genet)
1,120
Affymetrix 500k
Starr County Diabetes
study
Geneva NHS/HPFS
Diabetes study
Itsara et al.
1,794
Affymetrix 6.0
5,966
Affymetrix 6.0
2,493
Illumina Hap550,
Hap650Y and
Hap300
Zogopoulos et al. 2007 (Hum
Genet)
Below et al. 2011
(Diabetologia)
Qi et al. 2010 (Hum Mol
Genet)
Itsara et al. 2008 (Am J Hum
Genet)
Total
23,838
ISC et al.
3,181
Heinzen et al.
1,299
Total
4,480
Affymetrix 500k
and 6.0
Illumina 610Quad, 1 M,
Hap550, Hap317
2
chr15:28,536,722-30,664,276;
chr15:28,542,339-30,387,094
chr15:28,723,577-30,232,287;
chr15:28,730,804-30,389,965
0
0
0
0
0
1
chr15:28,707,916-30,402,925
0
1
chr15:28,816,548-30,231,488
0 deletions
7 duplications
ISC et al. 2008 (Nature)
0
-
Heinzen et al. 2010 (Am J
Hum Genet)
0
-
0
-
24
Table S7. Control dataset acknowledgments
Control datasets were obtained, along with permission for use, from the database of Genotypes and Phenotypes
(dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through accession numbers phs000143.v1.p1 (Starr County
Health Studies’ Genetics of Diabetes Study), phs000091.v2.p1 (GENEVA NHS/HPFS Diabetes study),
phs000169.v1.p1 (Whole Genome Association Study of Visceral Adiposity in the HABC Study),
phs000303.v1.p1 (Genetic Epidemiology of Refractive Error in the KORA Study) and phs000404.v1.p1
(COGEND; The Genetic Architecture of Smoking and Smoking Cessation). The Starr County Health Studies
Genetics of Diabetes Study was supported by the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) and the NIDDK Central Repositories. Support for the GWAS of Gene and Environment
Initiatives in Type 2 Diabetes was provided through the NIH Genes, Environment and Health Initiative [GEI]
(U01HG004399). The human subjects participating in the GWAS derive from The Nurses’ Health Study and
Health Professionals’ Follow-up Study and these studies are supported by National Institutes of Health (NIH)
grants CA87969, CA55075 and DK58845. Assistance with phenotype harmonization and genotype cleaning, as
well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA
Coordinating Center (U01 HG004446) and the National Center for Biotechnology Information. Support for
genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH GEI
(U01HG004424). Support for the ‘CIDR Visceral Adiposity Study’ was provided through the Division of
Aging Biology and the Division of Geriatrics and Clinical Gerontology, National Institute on Aging. Assistance
with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided
by Health ABC Study (HABC) Investigators. The KORA dataset was obtained from the NEI Refractive Error
Collaboration (NEIREC) Database, support for which was provided by the National Eye Institute. Support for
genotyping of the COGEND samples, which was performed at the Center for Inherited Disease Research
(CIDR), was provided by 1X01 HG005274-01. Assistance with genotype cleaning of the COGEND samples, as
well as with general study coordination, was provided by the Gene Environment Association Studies
(GENEVA) Coordinating Center (U01HG004446). Support for the collection of COGEND datasets and
samples was provided by the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392)
and the University of Wisconsin Transdisciplinary Tobacco Use Research Center (P50 DA019706, P50
CA084724).
25
Table S2 and S3 are available in excel format
from the Genetics in Medicine editorial office