Introduction: Short stature is one of the most common reasons for referral to a pediatric endocrinologist and can result from many etiologies. However, many patients with short stature do not receive a definitive diagnosis. Objective: To ascertain whether integrating targeted bioinformatics searches of electronic health records (EHRs) combined with genomic studies could identify patients with previously undiagnosed rare genetic etiologies of short stature. We focused on a specific rare phenotypic subgroup: patients with short stature and elevated IGF-I levels. Methods: We performed a cross-sectional cohort study at three large academic pediatric healthcare networks. Eligible subjects included children with heights below –2 SD, IGF-I levels >90th percentile, and no known etiology for short stature. We performed a search of the EHRs to identify eligible patients. Patients were then recruited for phenotyping followed by exome sequencing and in vitro assays of IGF1R function. Results: A total of 234 patients were identified by the bioinformatics algorithm with 39 deemed eligible after manual review (17%). Of those, 9 were successfully recruited. A genetic etiology was identified in 3 of the 9 patients including 2 novel variants in IGF1R and a de novo variant in CHD2. In vitro studies supported the pathogenicity of the IGF1R variants. Conclusions: This study provides proof of principle that patients with rare phenotypic subgroups can be identified based on discrete data elements in the EHRs. Although limitations exist to fully automating this approach, these searches may help find patients with previously unidentified rare genetic disorders.

1.
Dauber
A
,
Rosenfeld
RG
,
Hirschhorn
JN
.
Genetic evaluation of short stature
.
J Clin Endocrinol Metab
.
2014
Sep
;
99
(
9
):
3080
92
.
[PubMed]
0021-972X
2.
Sisley
S
,
Trujillo
MV
,
Khoury
J
,
Backeljauw
P
.
Low incidence of pathology detection and high cost of screening in the evaluation of asymptomatic short children
.
J Pediatr
.
2013
Oct
;
163
(
4
):
1045
51
.
[PubMed]
0022-3476
3.
Dean
BB
,
Lam
J
,
Natoli
JL
,
Butler
Q
,
Aguilar
D
,
Nordyke
RJ
.
Review: use of electronic medical records for health outcomes research: a literature review
.
Med Care Res Rev
.
2009
Dec
;
66
(
6
):
611
38
.
[PubMed]
1077-5587
4.
Cowie
MR
,
Blomster
JI
,
Curtis
LH
,
Duclaux
S
,
Ford
I
,
Fritz
F
, et al.
.
Electronic health records to facilitate clinical research
.
Clin Res Cardiol
.
2017
Jan
;
106
(
1
):
1
9
.
[PubMed]
1861-0684
5.
Kohane
IS
.
Using electronic health records to drive discovery in disease genomics
.
Nat Rev Genet
.
2011
Jun
;
12
(
6
):
417
28
.
[PubMed]
1471-0056
6.
Wolford
BN
,
Willer
CJ
,
Surakka
I
.
Electronic health records: the next wave of complex disease genetics
.
Hum Mol Genet
.
2018
May
;
27
R1
:
R14
21
.
[PubMed]
0964-6906
7.
Abuzzahab
MJ
,
Schneider
A
,
Goddard
A
,
Grigorescu
F
,
Lautier
C
,
Keller
E
, et al.;
Intrauterine Growth Retardation (IUGR) Study Group
.
IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation
.
N Engl J Med
.
2003
Dec
;
349
(
23
):
2211
22
.
[PubMed]
0028-4793
8.
David
A
,
Hwa
V
,
Metherell
LA
,
Netchine
I
,
Camacho-Hübner
C
,
Clark
AJ
, et al.
.
Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity
.
Endocr Rev
.
2011
Aug
;
32
(
4
):
472
97
.
[PubMed]
0163-769X
9.
Walenkamp
MJ
,
Robers
JM
,
Wit
JM
,
Zandwijken
GR
,
van Duyvenvoorde
HA
,
Oostdijk
W
, et al.
.
Phenotypic Features and Response to GH Treatment of Patients With a Molecular Defect of the IGF-1 Receptor
.
J Clin Endocrinol Metab
.
2019
Aug
;
104
(
8
):
3157
71
.
[PubMed]
0021-972X
10.
Walenkamp
MJ
,
Losekoot
M
,
Wit
JM
.
Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management
.
Endocr Dev
.
2013
;
24
:
128
37
.
[PubMed]
1421-7082
11.
Yang
L
,
Xu
DD
,
Sun
CJ
,
Wu
J
,
Wei
HY
,
Liu
Y
, et al.
.
IGF1R variants in patients with growth impairment: four novel variants and genotype-phenotype correlations
.
J Clin Endocrinol Metab
.
2018
Nov
;
103
(
11
):
3939
44
.
[PubMed]
0021-972X
12.
Wang
SR
,
Carmichael
H
,
Andrew
SF
,
Miller
TC
,
Moon
JE
,
Derr
MA
, et al.
.
Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature
.
J Clin Endocrinol Metab
.
2013
Aug
;
98
(
8
):
E1428
37
.
[PubMed]
0021-972X
13.
Storr
HL
,
Dunkel
L
,
Kowalczyk
J
,
Savage
MO
,
Metherell
LA
.
Genetic characterisation of a cohort of children clinically labelled as GH or IGF1 insensitive: diagnostic value of serum IGF1 and height at presentation
.
Eur J Endocrinol
.
2015
Feb
;
172
(
2
):
151
61
.
[PubMed]
0804-4643
14.
Finken
MJ
,
van der Steen
M
,
Smeets
CC
,
Walenkamp
MJ
,
de Bruin
C
,
Hokken-Koelega
AC
, et al.
.
Children born small for gestational age: differential diagnosis, molecular-genetic evaluation and implications
.
Endocr Rev
.
2018
Dec
;
39
(
6
):
851
94
.
[PubMed]
0163-769X
15.
Kuczmarski
RJ
,
Ogden
CL
,
Guo
SS
,
Grummer-Strawn
LM
,
Flegal
KM
,
Mei
Z
, et al.
.
2000 CDC Growth Charts for the United States: methods and development
.
Vital Health Stat 11
.
2002
May
;(
246
):
1
190
.
[PubMed]
0083-1980
16.
Bidlingmaier
M
,
Friedrich
N
,
Emeny
RT
,
Spranger
J
,
Wolthers
OD
,
Roswall
J
, et al.
.
Reference intervals for insulin-like growth factor-1 (igf-i) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations
.
J Clin Endocrinol Metab
.
2014
May
;
99
(
5
):
1712
21
.
[PubMed]
0021-972X
17.
de Bruin
C
,
Mericq
V
,
Andrew
SF
,
van Duyvenvoorde
HA
,
Verkaik
NS
,
Losekoot
M
, et al.
.
An XRCC4 splice mutation associated with severe short stature, gonadal failure, and early-onset metabolic syndrome
.
J Clin Endocrinol Metab
.
2015
May
;
100
(
5
):
E789
98
.
[PubMed]
0021-972X
18.
Fang
P
,
Schwartz
ID
,
Johnson
BD
,
Derr
MA
,
Roberts
CT
Jr
,
Hwa
V
, et al.
.
Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay
.
J Clin Endocrinol Metab
.
2009
May
;
94
(
5
):
1740
7
.
[PubMed]
0021-972X
19.
Fang
P
,
Cho
YH
,
Derr
MA
,
Rosenfeld
RG
,
Hwa
V
,
Cowell
CT
.
Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R)
.
J Clin Endocrinol Metab
.
2012
Feb
;
97
(
2
):
E243
7
.
[PubMed]
0021-972X
20.
Carvill
GL
,
Heavin
SB
,
Yendle
SC
,
McMahon
JM
,
O’Roak
BJ
,
Cook
J
, et al.
.
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
.
Nat Genet
.
2013
Jul
;
45
(
7
):
825
30
.
[PubMed]
1061-4036
21.
Petersen
AK
,
Streff
H
,
Tokita
M
,
Bostwick
BL
.
The first reported case of an inherited pathogenic CHD2 variant in a clinically affected mother and daughter
.
Am J Med Genet A
.
2018
Jul
;
176
(
7
):
1667
9
.
[PubMed]
1552-4825
22.
Suls
A
,
Jaehn
JA
,
Kecskés
A
,
Weber
Y
,
Weckhuysen
S
,
Craiu
DC
, et al.;
EuroEPINOMICS RES Consortium
.
De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome
.
Am J Hum Genet
.
2013
Nov
;
93
(
5
):
967
75
.
[PubMed]
0002-9297
23.
Kulkarni
S
,
Nagarajan
P
,
Wall
J
,
Donovan
DJ
,
Donell
RL
,
Ligon
AH
, et al.
.
Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis
.
Am J Med Genet A
.
2008
May
;
146A
(
9
):
1117
27
.
[PubMed]
1552-4825
24.
Hauer
NN
,
Popp
B
,
Schoeller
E
,
Schuhmann
S
,
Heath
KE
,
Hisado-Oliva
A
, et al.
.
Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature
.
Genet Med
.
2018
Jun
;
20
(
6
):
630
8
.
[PubMed]
1098-3600
25.
Walenkamp
MJ
,
de Muinck Keizer-Schrama
SM
,
de Mos
M
,
Kalf
ME
,
van Duyvenvoorde
HA
,
Boot
AM
, et al.
.
Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2-[{GT}]qter deletion detected by multiplex ligation probe amplification
.
J Clin Endocrinol Metab
.
2008
Jun
;
93
(
6
):
2421
5
.
[PubMed]
0021-972X
26.
Lango Allen
H
,
Estrada
K
,
Lettre
G
,
Berndt
SI
,
Weedon
MN
,
Rivadeneira
F
, et al.
.
Hundreds of variants clustered in genomic loci and biological pathways affect human height
.
Nature
.
2010
Oct
;
467
(
7317
):
832
8
.
[PubMed]
0028-0836
27.
Walenkamp
MJ
,
van der Kamp
HJ
,
Pereira
AM
,
Kant
SG
,
van Duyvenvoorde
HA
,
Kruithof
MF
, et al.
.
A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor
.
J Clin Endocrinol Metab
.
2006
Aug
;
91
(
8
):
3062
70
.
[PubMed]
0021-972X
28.
Kruis
T
,
Klammt
J
,
Galli-Tsinopoulou
A
,
Wallborn
T
,
Schlicke
M
,
Müller
E
, et al.
.
Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation
.
J Clin Endocrinol Metab
.
2010
Mar
;
95
(
3
):
1137
42
.
[PubMed]
0021-972X
29.
Nagel
BH
,
Mortier
W
,
Elmlinger
M
,
Wollmann
HA
,
Schmitt
K
,
Ranke
MB
.
Short stature in Duchenne muscular dystrophy: a study of 34 patients
.
Acta Paediatr
.
1999
Jan
;
88
(
1
):
62
5
.
[PubMed]
0803-5253
30.
Miell
JP
,
Taylor
AM
,
Jones
J
,
Holly
JM
,
Gaillard
RC
,
Pralong
FP
, et al.
.
The effects of dexamethasone treatment on immunoreactive and bioactive insulin-like growth factors (IGFs) and IGF-binding proteins in normal male volunteers
.
J Endocrinol
.
1993
Mar
;
136
(
3
):
525
33
.
[PubMed]
0022-0795
31.
Rosenfeld
RG
.
Genetic Diagnosis of Growth Failure. Genetic Diagnosis of Endocrine Disorders
. 2nd ed.
Academic Press, Elsevier
;
2016
.
You do not currently have access to this content.