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Received: 24 August 2018
DOI: 10.1002/mgg3.992
Revised: 28 August 2019
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Accepted: 3 September 2019
CLINICAL REPORT
Exome sequencing study of partial agenesis of the corpus
callosum in men with developmental delay, epilepsy, and
microcephaly
Jolyane Meloche1,2
Marie‐Ève Lavoie
Charles Morin
3
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1,2
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Vanessa Brunet2
Pierre‐Alexandre Gagnon1,2
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3
Jean‐Benoît Bouchard
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Javad Nadaf
4
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Jacek Majewski4
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1,2
Catherine Laprise
1
Centre intersectoriel en santé
durable, Université du Québec à
Chicoutimi, Saguenay, QC, Canada
2
Département des Sciences
Fondamentales, Université du Québec à
Chicoutimi, Saguenay, QC, Canada
3
Centre de Santé et de Services Sociaux de
Chicoutimi, Saguenay, QC, Canada
4
Department of Human Genetics, McGill
University and Genome Quebec Innovation
Centre, Montreal, QC, Canada
Correspondence
Catherine Laprise, Centre intersectoriel en
santé durable, Département des sciences
fondamentales, Université du Québec à
Chicoutimi, Saguenay, Québec G7H 2B1,
Canada.
Email: catherine.laprise@uqac.ca
Funding information
Fondation Louis‐Philippe Gagnon
Abstract
Background: This study reports the genetic features of four Caucasian males from
the Saguenay‒Lac‐St‐Jean region affected by partial agenesis of the corpus callosum
(ACC) with hypotonia, epilepsy, developmental delay, microcephaly, hypoplasia,
and autistic behavior.
Methods: We performed whole exome sequencing (WES) to identify new genes
involved in this pathological phenotype. The regions of interest were subsequently
sequenced for family members.
Results: Single‐nucleotide variations (SNVs) and insertions or deletions were detected in genes potentially implicated in brain defects observed in these patients.
One patient did not have mutations in genes related to ACC, but carried a de novo
pathogenic mutation in Mucolipin‐1 (MCOLN1) and was diagnosed with mucolipidosis type IV. Among the other probands, missense SNVs were observed in DCLK2
(Doublecortin Like Kinase 2), HERC2 (HECT And RLD Domain Containing E3
Ubiquitin Protein Ligase 2), and KCNH3 (Potassium channel, voltage‐gated, subfamily H, member 3). One patient also carried a non‐frameshift insertion in CACNA1A
(Cav2.1(P/Q‐type) calcium channels).
Conclusion: Although no common genetic defect was observed in this study, we
provide evidence for new avenues of investigation for ACC, such as molecular pathways involving HERC2, CACNA1A, KCNH3, and more importantly DCLK2. We
also allowed to diagnose an individual with mucolipidosis type IV.
KEYWORDS
agenesis of the corpus callosum, DCLK2, exome sequencing, genetics
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Mol Genet Genomic Med. 2020;8:e992.
https://doi.org/10.1002/mgg3.992
wileyonlinelibrary.com/journal/mgg3
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IN T RO D U C T ION
The corpus callosum is the largest white matter tract in the
human brain (Mihrshahi, 2006). It is essential for communication as it coordinates and transfers information between the
two cerebral hemispheres (Aboitiz & Montiel, 2003). It plays
a critical role in cognition, as well as in various sensory and
motor functions (Mihrshahi, 2006). As early as 6 weeks of
gestation, the 200 million axons that will become the corpus
callosum are growing within the hemispheres. These fibers
will start closing the gap between the 11th and 12th week of
gestation. The partial or complete absence of this commissure is called a partial or complete agenesis of the corpus callosum (ACC). ACC is among the most frequent human brain
malformations, occurring in 1:4000 individuals (Paul et al.,
2007). Although the exact mechanisms implicated in ACC
etiology are unknown, current evidence suggests that genetic
alterations, such as single gene mutation or more complex
genetic abnormalities, are implicated in its development.
The Saguenay–Lac‐St‐Jean (SLSJ) region is in the
northeastern Quebec in Canada. Most of the SLSJ population is of French‐Canadian descent and this region was
marked by three successive founder effects, which contributed to shape its unique genetic pool (De Braekeleer,
Dallaire, & Mathieu, 1993). Because of this, several genetic disorders have been described in this population, such
as the hereditary motor and sensory neuropathy associated
with ACC, known as the Andermann syndrome.(OMIM
#218000) This syndrome was described in 1972 in patients
originating from the SLSJ and Charlevoix regions (Dupre
et al., 2003; Larbrisseau, Vanasse, Brochu, & Jasmin,
1984). This disorder was classified as an autosomal recessive syndrome affecting the chromosomal region 15q13‐15
(SLC12A6, OMIM #604878) and characterized by ACC associated with a progressive motor neuropathy.
More recently, physicians noticed that some children
affected by partial ACC in the SLSJ region had a specific
phenotype. Their ACC was not associated with Andermann
syndrome or other syndromes commonly associated with
ACC (Bedeschi et al., 2006; Taylor & David, 1998; van Bon
et al., 2008; Volpe et al., 2006). In contrast, they had a specific phenotype: partial ACC associated with microcephaly,
hypoplasia, developmental delay, epilepsy, and autistic behavior. In this context, we hypothesized that there might be
a common genetic disorder causing this pathological phenotype involving epilepsy, developmental delay, microcephaly,
hypoplasia, as well as partial ACC. Consequently, the objective of this study was to define common genes and/or variations implicated in this pathological phenotype using whole
exome sequencing (WES) on several individuals presenting
these clinical symptoms. As shown by Topper et al., WES is
a promising technique for identifying new genes involved in
intellectual disability (Topper, Ober, & Das, 2011).
2
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M ATERIAL S AND M ETHOD S
2.1 | Editorial policies and ethical
considerations
Ethical approval was obtained from the appropriate institutional ethic committees (Centre intégré universitaire de santé
et de services sociaux (CIUSSS) du SLSJ and Université du
Québec à Chicoutimi (UQAC)) and all individuals gave written informed consent.
2.2
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Sample selection
Following the genetic structure of the population of SLSJ,
known for its founder effect (Scriver, 2001), we included
patients with partial ACC associated with epilepsy (refractory seizures; mixed generalized or partial focal to bilateral
tonic‐clonic seizures), delayed psychomotor development,
microcephaly (head circumference at birth <3rd percentile), midfacial hypoplasia, low hair implantation, autism
or autistic behavior, and with at least one grandparent
native of SLSJ. These patients presented isolated partial
ACC, as they did not have any other central nervous system
disorders. At the neuropsychological level, all probands
exhibited a profound intellectual retardation. These clinical characteristics will be considered as the “pathological
phenotype.” The exclusion criteria were the presence of
polyneuropathy and/or a chromosomal abnormality already
documented. Medical files of all minors with these specific
symptoms and their relatives were obtained from the participating medical center archives and were reviewed. A
total of four patients with similar clinical characteristics
were included in this study (Table 1). We also included
parents of the patients with ACC, as well as their sibling
(brothers in these cases), when possible, to compare genotypes. All probands were Caucasian males.
2.3
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Exome sequencing
DNA was extracted from blood samples of four probands
and their relatives (parents, as well as brother when available) using the Blood & Cell Culture DNA Mini Kit
(QIAGEN) according to the manufacturer's instructions.
WES was performed on the four affected individuals at the
McGill University and Genome Québec Innovation Center.
Exome capture was performed with the SureSelect® High
Throughput Library from Agilent (Agilent Technologies).
Exon‐enriched DNA was then sequenced with the
HiSeq2000 Illumina technology. Libraries were sequenced
in paired‐end formats for read lengths of 100 base pairs.
The sequencing reads were aligned to the NCBI human
reference genome (NCBI, build GRCh37/hg19) using
Burrows‐Wheeler Alignment tool (BWA) (Li & Durbin,
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MELOCHE ET AL.
TABLE 1
Clinical and phenotypic
data of the probands
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Clinical features shared by all probands
(inclusion criteria)
Other diseases and medical condition
•
•
•
•
•
•
•
•
•
• Attention deficit hyperactivity disorder
• Alternate esotropia
(strabismus)
• Behavioral disorder
• Eczema
• Negative Angelman test
• Pityriasis rosea
• Gastritis
Patient
Age
1
23
2
21
• Hyperactivity
• Growth retardation at
birth
• Delayed language
3
40
• Anemia
• Major handicap (no
words)
• Hypomagnesaemia
• Folic acid deficit
• Cerebral palsy
• Spastic quadriplegia
• Bowel obstruction
• Volvulus
• Scoliosis
4
18
• Thoracic convexity to
the right
• Fulminant hepatitis
• Asthma and food
allergies
• Growth retardation at
birth
2009). Single‐nucleotide variations (SNVs) and small insertions and deletions (INDELs) were subsequently identified using VarScan. ANNOVAR (open bioinformatics) was
used to classify and annotate variants (INDELs, SNVs).
SIFT (Sorting Intolerant From Tolerant) and PolyPhen‐2
(Polymorphism Phenotyping v2) were used to assess the potential pathogenicity of nonsynonymous variants (Adzhubei
et al., 2010; Ng & Henikoff, 2001). ExAC Browser was used
to investigate the probability of loss of function intolerance
for the candidate genes (Lek et al., 2016).
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Bioinformatic filtering
Stringent thresholds were used for variant calling. Variants
in sites covered at less than 10×, variants in sites covered
in only one direction, as well as variants found in <4 reads
or <5% of reads were excluded. Further variant filtering
was performed: nongenic, intronic, and synonymous variants were excluded from our analyses. SNVs found in >1%
controls when compared to the 1000 Genome Project,
Partial agenesis of the corpus callosum
Hypotonia
Epilepsy
Autistic behavior
Delayed psychomotor development
Midfacial hypoplasia
Microcephaly
Absence of polyneuropathy
Absence of known chromosomal
abnormalities
dbSNP, and the Réseau de Médecine Génétique Appliquée
(Genome Quebec, Genome Canada) databases were excluded from this study. Among these, variants including
splice variants, deletions, and truncating SNVs, that were
predicted pathogenic (SIFT, PolyPhen‐2), were kept for
analyses. Furthermore, to find a potential gene responsible
for the pathogenic characteristics of these probands with
ACC, we focused our research on genes involved in the development and/or the integrity of motoneurons based on a
thorough search of the literature. Genes that were biologically relevant to the pathological phenotype were selected
for the next steps.
2.5
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Sanger sequencing
After narrowing our search to variants in genes known to
play a role in the development or integrity of motoneurons,
DNA sequencing for the region of interest in these genes
was performed by Sanger sequencing at the Plateforme
de Séquençage et de Génotypage des Génomes (Centre
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Hospitalier Universitaire de Québec‐Université Laval,
Québec, Canada). This step was performed on DNA of the
affected individual, as well as his parents and siblings (when
possible) to confirm variants, and to identify their transmission patterns, or if they are de novo mutations.
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R E S U LTS
To find impactful genes responsible for the pathogenic
characteristics of these probands with partial ACC, WES
analyses were performed and variations in genes involved
in the development and/or the integrity of motoneurons were
prioritized. With this stringent filtering process, no variation was common to all probands. Nevertheless, variations
in four genes with potential biological implication on the
development and/or integrity of motoneurons were identified in three of the four affected men (Table 2). Indeed,
variations in DCLK2 (Doublecortin Like Kinase 2, OMIM
#613166), HERC2 (HECT And RLD Domain Containing
E3 Ubiquitin Protein Ligase 2, OMIM #605837), KCNH3
(Potassium channel, voltage‐gated, subfamily H, member
3, OMIM #604527), and CACNA1A (calcium voltage‐gated
channel subunit alpha1 A, OMIM #601011) were observed.
Furthermore, Sanger sequencing was performed on DNA
from the probands' parents to distinguish the transmission
pattern or whether it is a de novo mutation. DNA from
healthy siblings, brothers in both cases, also underwent sequencing to investigate whether they inherited these variations. This helped in shedding light on the potential clinical
impact of these variations.
Variations in HERC2 (coding for HECT And RLD
Domain Containing E3 Ubiquitin Protein Ligase 2), which
is often associated with neurodevelopmental disorders,
(Cubillos‐Rojas et al., 2016; Puffenberger et al., 2012; Tan,
Bird, Thibert, & Williams, 2014) are relevant for one case
(patient 1). This proband is heterozygous for three SNVs in
this gene (rs765206957 (NC_000015.9:g.28380739T>C),
rs757141755 (NC_000015.9:g.28391439C>T), rs138059246
(NC_000015.9:g.28459392G>A)), which were inherited
from either one of his parents (Table 2). Thus, this proband
has three multiple heterozygous variations in the HERC2,
which may impact HERC2 expression and protein production. Using PolyPhen‐2, the possible impact of amino acid
substitution on protein function was predicted (Adzhubei et
al., 2010). The impact of nonsynonymous variations is based
on sequence homology and physical properties of amino
acids (Table 2). According to PolyPhen‐2, two of these three
SNVs are thought to be probably damaging the protein function. Nevertheless, his mother is homozygous for both these
variations. The proband's brother (healthy) carries the same
genetic profile for HERC2, as both siblings are heterozygous
for these three variations (Figure 1).
Our analyses also pointed out two variations in
the DCLK2 (coding for Doublecortin Like Kinase
2) in another proband (patient 2). A missense variation (rs200222469 (NC_000004.11:g.151000277G>A,
NC_000004.11:g.151000277G>T)) was identified along
with another nonsynonymous SNV in DCLK2 in this patient. Very little information is known on this second SNV
at position chr4:151170745 (p.Met661Lys). Interestingly, the
proband is the only family member affected by both these
variations (Table 2 and Figure 1).
Furthermore, variations in two other genes were observed
in our probands with the pathological phenotype. Patient 3
holds a non‐frameshift insertion in the CACNA1A, encoding for calcium voltage‐gated channel subunit alpha1 A. He
also carries two variations in KCNH3, which encodes for the
potassium channel, voltage‐gated, subfamily H, member 3.
Nevertheless, this proband inherited these KCNH3 variations
from his mother. Unfortunately, we were unable to determine
the transmission pattern for the variation in CACNA1A since
adequate PCR amplification for this gene was impossible due
to the nucleotide sequence specificities and difficulties in
performing the technique.
Although, one patient (patient 4) did not have mutations
in genes related to ACC, this study showed that he carried
a de novo pathogenic mutation in Mucolipin‐1 (MCOLN1).
A Mucolipidosis type IV diagnostic was made by a clinician and subsequent genetic counseling and screening was
offered to the paternal family of this proband since one
disease‐associated allele, based on ClinVar (rs148748724
(NC_000019.9:g.7591493G>A)), was transmitted by his
father (Table 2). Another patient (patient 1) also carried a
variation in MCOLN1, but this nonsynonymous variation is
potentially benign according to PolyPhen‐2 (Polymorphism
Phenotyping v2) prediction tool (Adzhubei et al., 2010).
Thus, sequencing was not performed for this region of the
gene.
4
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DISCUSSION
Clinical manifestations of ACC, a common abnormality in
the brain structure, vary from asymptomatic to delayed development, hypotonia, epilepsy, and microcephaly. In the
SLSJ region, several pediatricians noticed that patients with
partial ACC without polyneuropathy had hypotonia and later
presented epilepsy, developmental delay, microcephaly,
midfacial hypoplasia, low hair implantation, and autistic behavior (Table 1). WES was performed on four probands with
the pathological phenotype and rare variants (<1%) in genes
involved in the development and/or the integrity of motoneurons were highlighted. Although we were not able to identify a novel susceptibility variant for ACC in this study, we
provide evidence for new avenues of investigation, such as
MELOCHE ET AL.
TABLE 2
Mutations and polymorphisms resulting in amino acid changes in genes potentially implicated in agenesis of the corpus callosum in affected men
Impact
(PolyPhen‐2,
SIFT)
Patient
Gene
SNP ID
HGVS
Frequency
(ExAC)
1
MCOLN1
rs73003348
NC_000019.9:g.7593048C>T
3.04E‐03
missense SNV
p.Thr261Met
Benign,
tolerated
CT
HERC2
rs765206957
NC_000015.9:g.28380739T>C
4.94E‐05
missense SNV
p.Ile4039Val
Possibly
damaging
rs757141755
NC_000015.9:g.28391439C>T
2.47E‐05
missense SNV
p.Arg3651His
rs138059246
NC_000015.9:g.28459392G>A
8.57E‐04
missense SNV
rs200222469
NC_000004.11:g.151000277G>A
NC_000004.11:g.151000277G>T
1.89E‐04
NA
NC_000004.11:g.151170745T>A
CACNA1A
NA
KCNH3
2
3
4
DCLK2
MCOLN1
Maternal
genotype
Paternal
genotype
Sibling
genotype
CT
TT
CT
CT
Probably
damaging
CT
TT
CC
CT
p.Arg2129Cys
Probably
damaging
AG
AA
GG
AG
missense SNV
p.Gly33Val
Benign,
tolerated
GT
GT
GG
GT
NA
missense SNV
p.Met661Lys
Probably
damaging
AT
TT
AT
TT
NA
NA
non‐frameshift
insertion
p.Pro2312_
Gln2313ins
unknown
possible
homozygous
NA
NC_000012.11:g.49936607G>T
NA
missense SNV
p.Lys188Asn
Possibly
damaging
GT
GT
GG
NA
NC_000012.11:g.49936608C>T
NA
missense SNV
p.His189Tyr
Possibly
damaging
CT
CT
CC
rs148748724
NC_000019.9:g.7591493G>A
2.48E‐05
splice donor
c.405+1G>A
Pathogenic
AA (de novo
mutation)
GG
AG
Variation
Consequence
Proband
genotype
Abbreviations: CACNA1A, calcium voltage‐gated channel subunit alpha1 A; DCLK2, Doublecortin Like Kinase 2; ExAC, Exome Aggregation Consortium; HERC2, HECT And RLD Domain Containing E3 Ubiquitin Protein
Ligase 2; HGVS, The Human Genome Variation Society Nomenclature; KCNH3, Potassium channel, voltage‐gated, subfamily H, member 3; MCOLN1, Mucolipin‐1; NA, data not available; PolyPhen‐2, Polymorphism
Phenotyping v2; SIFT, Sorting Intolerant From Tolerant; SNP ID, single‐nucleotide polymorphism database identification; SNV, Single‐nucleotide variation.
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F I G U R E 1 Genetic pedigrees of
the four probands in this study. DCLK2,
Doublecortin‐Like Kinase 2; HERC2,
HECT And RLD Domain Containing
E3 Ubiquitin Protein Ligase 2; KCNH3,
Potassium channel, voltage‐gated, subfamily
H, member 3; MCOLN1, Mucolipin‐1
molecular pathways involving HERC2, CACNA1A, KCNH3,
and more importantly DCLK2. Indeed, the four probands,
although they exhibit similar clinical characteristics, do not
share a common genetic disorder. It is also possible that a
common mutation was not discovered using WES, since this
technique only covers exons. These analyses allowed to identify that, in most cases, at least one parent is a heterozygous
carrier for the variations found in their affected child (Figure
1). Thus, further studies and functional assays are required
to clearly understand whether these genes play a role in the
development of ACC.
The implication of HERC2 might not be surprising because
of its implication in developmental delay, autism spectrum
disorder, as well as Angelman‐like features (Puffenberger et
al., 2012; Tan et al., 2014). Indeed, both studies identified a
missense mutation in HERC2 (rs397518474). Nevertheless,
this mutation was not observed in patient 1 (Table 2). In another study, mutations in HERC2 were associated with three
cases of absence of the posterior half of the corpus callosum
(Harlalka et al., 2013). In our study, although the proband's
brother carries the same genotype for the HERC2, reduced
penetrance and variable expressivity may affect the pattern
of inheritance and may contribute to explain why only one
sibling is affected by the disease. Further investigation is
mandatory to demonstrate the pathogenic implication of the
mutations found in this patient.
KCNH3 is mainly expressed in the brain and was previously associated with cognitive function (Miyake et al.,
2009). These alterations in cognitive function were also
observed in KCNH3 heterozygous mutant mice. Taken together, these alterations may impact the development and/
or progression of ACC and associated disorders observed in
this proband. Nevertheless, the affected child shares these
mutations with his mother. Thus, taken alone, these mutations do not seem to induce ACC since the mother is not
affected by this disease. More studies will be needed to demystify the underlying mechanisms involved in the types of
interaction that regulate the genetics of this complex disease
since the mutations potentially implicated in ACC development in patients 1 and 3 do not show regular segregation
patterns, as concordance between genotypes and phenotypes
is not always present.
Our results also pointed out the potential implication of
the calcium channel CACNA1A. In the literature, a missense mutation in CACNA1A was observed in a patient
affected by encephalopathy with a thin corpus callosum
(Hayashida et al., 2018). Although our proband was not
affected by the same mutation, a non‐frameshift insertion
may alter the calcium channel formation and impact the
development of ACC. Moreover, alterations in another isoform of this calcium channel were associated with ACC
in a study by Sajan et al. (2013). They reported that rare
copy number variants in CACNA1B could be considered
as genetic risk factors in ACC patients. Furthermore,
Damaj et al. also demonstrated that some patients carrying
CACNA1A mutations develop epilepsy, autism, and cognitive impairment (Damaj et al., 2015). Thus, functional studies should be conducted to pinpoint the role of CACNA1A
in the pathophysiology of ACC.
Regarding the implication of DCLK mutations, mice
studies exhibited a role for DCLK in cortical neuronal migration and commissure formation. Deuel et al. showed that
Dclk mutant mice exhibit axonal defects, which affected
the corpus callosum (Deuel et al., 2006). Patient 2 holds
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MELOCHE ET AL.
missense mutations in DCLK, which could impact the development and/or progression of ACC and related disorders in
this affected patient. Interestingly, the rs200222469 variant
was reported in a patient with ACC in Geno2MP, a database
of rare variants from the University of Washington Center
for Mendelian Genomics (UW‐CMG). Furthermore, this
proband is the only family member affected by both these
mutations. Thus, this compound heterozygosity could have
had a detrimental effect on the corpus callosum and unfortunately lead to ACC development by altering this serine/
threonine‐protein kinase.
In conclusion, although the probands exhibited the same
pathological phenotype, they do not seem to be affected by
a common genetic disorder, but rather a combination of several diseases or syndromes presenting common clinical signs.
Although our findings do not suggest a common ACC susceptibility gene, they provide new insights into molecular
pathways involving HERC2, CACNA1A, KCNH3, and more
interestingly DCLK2 that could possibly be implicated in
ACC development since they are all key players in motoneurons development and integrity.
ACKNOWLEDGMENTS
We thank the patients and their families for their valuable participation in this study. We also thank collaborators, especially
the Plateforme de Séquençage et de Génotypage des Génomes
of Quebec City, as well as the funding agencies. Jolyane
Meloche received a Fonds de recherche du Québec ‒ Santé
Postdoctoral training scholarship. This project was supported
by the Fondation Louis‐Philippe Gagnon and operating grants
from the Canadian Institute of Health Research (CIHR).
Catherine Laprise is the co‐director of the Environment /
Genetic / Cancer research axis of the Respiratory Health
Network (RHN), investigator of CHILD Study and is a member of the AllerGen NCE Inc. and the chairholder of the
Canada Research Chair in the Environment and Genetics of
Respiratory Disorders and Allergies (www.chairs.gc.ca).
CONFLICT OF INTEREST
None.
ORCID
Jolyane Meloche
https://orcid.org/0000-0001-5234-2326
R E F E R E NC E S
(UW‐CMG), N. N. U. o. W.‐C. f. M. G. Geno2MP. http://geno2mp.gs.
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How to cite this article: Meloche J, Brunet V, Gagnon
P‐A, et al. Exome sequencing study of partial agenesis
of the corpus callosum in men with developmental
delay, epilepsy, and microcephaly.
Mol Genet Genomic Med. 2020;8:e992. https://doi.
org/10.1002/mgg3.992