European Journal of Medical Genetics 63 (2020) 103850

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European Journal of Medical Genetics

journal homepage: www.elsevier.com/locate/ejmg

Jumonji domain containing 1C (JMJD1C) sequence variants in seven T

patients with autism spectrum disorder, intellectual disability and seizures
Anne Slavotineka,∗, Johanna M. van Hagenb, Louisa Kalsnerc, Shashidhar Paid,
Laura Davis-Keppene, Lisa Ohdenf, Yvonne G. Weberg, Erica L. Mackeh, Eric W. Kleeh,i,
Eva Moravah,i, Lauren Gundersoni, Richard Personj, Shuxi Liuj, Marjan Weissb
a
Dept. Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA, 94143-2711, USA
b
Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, De Boelelaan 1117, Amsterdam, the Netherlands
c
Departments of Pediatrics and Neurology, Connecticut Children's Medical Center and University of Connecticut Health Center, Farmington, CT, USA
d
Medical University of South Carolina Health, Charleston, SC, USA
e
University of South Dakota Sanford School of Medicine and Sanford Children's Hospital, Sioux Falls, SD, USA
f
Sanford Children's Hospital and Specialty Clinic, Sioux Falls, SD, USA
g
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
h
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA
i
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
j
GeneDx, Gaithersburg, MD, USA

A R T I C LE I N FO A B S T R A C T

Keywords: The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C
Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that
JMJD1C is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability
Autism spectrum disorder and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were
Intellectual disability
no consistent additional findings. Two patients were reported to have seizures for which there was no other
identified cause. De novo, deleterious sequence variants in JMJD1C have previously been reported in patients
with autism spectrum disorder and a phenotype resembling classical Rett syndrome, but only one JMJD1C
variant has undergone functional evaluation. In all of the seven patients in this report, there was a plausible,
alternative explanation for the neurocognitive phenotype or a modifying factor, such as an additional potentially
pathogenic variant, presence of the variant in a population database, heteroplasmy for a mitochondrial variant
or mosaicism for the JMJD1C variant. Although the de novo variants in JMJD1C are likely to be relevant to the
developmental phenotypes observed in these patients, we conclude that further data supporting the association
of JMJD1C variants with intellectual disability is still needed.

1. Introduction deleterious sequence variants in JMJD1C have been previously reported

The Jumonji domain containing 1C (JMJD1C) gene encodes the
Jumonji domain-containing protein 1C (JMJD1C) which a member of
the jmJC domain-containing protein family that is involved in histone
demethylation (Guo et al., 2015; Sáez et al., 2016). The gene is widely
expressed in the brain. In response to DNA damage, JMJD1C interacts
with Ring finger protein 8 (RNF8) and demethylates the mediator of
DNA damage checkpoint protein 1 (MDC1) at Lys45, promoting an
interaction between MDC1 and ring finger protein 8 (RNF8) that results
in RNF8-mediated ubiquitylation of MDC1 around double strand break
sites (Lu and Matunis, 2013; Watanabe et al., 2013). De novo,
in a patient with a phenotype resembling classical Rett syndrome and in
two patients with autism spectrum disorder (Neale et al., 2012; Iossifov
et al., 2014; Sáez et al., 2016). Functional studies were performed for
the missense variant, p.(Pro163Leu), that was identified in the patient
with manifestations similar to Rett syndrome and the altered protein
demonstrated abnormal subcellular localization, reduced MECP2
binding and reduced ability to demethylate MDC1. Two other case re-
ports described chromosome aberrations disrupting or causing hap-
loinsufficiency for JMJD1C in children with intellectual disability
(Castermans et al., 2007; Shimojima et al., 2017). However, the full
extent of the phenotypic features and spectrum of deleterious variants

∗
Corresponding author.
E-mail address: anne.slavotinek@ucsf.edu (A. Slavotinek).

https://doi.org/10.1016/j.ejmg.2020.103850
Received 17 February 2019; Received in revised form 26 November 2019; Accepted 12 January 2020
Available online 16 January 2020
1769-7212/ © 2020 Elsevier Masson SAS. All rights reserved.
A. Slavotinek, et al.
in this gene are unknown. Herein we report seven, unrelated patients
with developmental delays or intellectual disability and de novo, het-
erozygous sequence variants in JMJD1C.
2. Clinical reports
Clinicians were contacted after matching in GeneMatcher (Sobreira
et al., 2015). Written informed consent for sequencing was obtained
from all patients. Medical history and phenotypic features were ex-
tracted from health records as per standard clinical practice.
2.1. Patient 1
Patient 1 was a male who was 11 years and 11 months old at the
time of reporting. He was the second child of healthy, non-con-
sanguineous parents. The pregnancy was uncomplicated and he was
delivered at 40 weeks of gestation with the umbilical cord around the
neck and with meconium staining of the amniotic fluid. Birthweight
was 3,750 g (50-75th centile) and length was 56 cm (> 97th centile).
Apgar scores were 8 and 10 at one and five minutes respectively. The
neonatal period was notable for frequent crying and reflux. He had
strabismus, but his vision and hearing were normal. His milestones
were delayed and he first walked independently at two years of age and
spoke his first words at two and a half years of age, resulting in diag-
noses of intellectual disability, autism spectrum disorder and attention
deficit hyperactivity disorder. At 14 years of age, WISC-III showed a
verbal IQ of 82 (range 76–91), performance IQ of 71 (range 66–86) and
a total IQ of 75 (range 69–84). On examination at 11 years and 11
months of age, occipitofrontal circumference (OFC) was 55 cm (+0.53
SD; length was 158 cm (mean to +0.42 SD); and weight was 37 kg
(−1.80 SD, weight/length). There were no dysmorphic features. A
magnetic resonance imaging (MRI) scan of the brain was not per-
formed.
2.2. Patient 2
Patient 2 was delivered at 39 weeks of gestation to a 36 year old,
G3P2-3 mother with a birthweight of 3,005 g (10–25th centile). The
baby had hypotonia early in life that has slowly improved and she first
walked independently at 18 months of age. Her speech was delayed and
she had full sentences in first grade. She received special education with
occupational therapy and adaptive physical education from two years
of age until 4th grade and she was around one year behind her peers
when she started Kindergarten. She also received resource classes for
1.5–2 hours per day at school. A developmental assessment at 10 years
of age showed a verbal comprehension score of 87 (19th centile),
perceptual reasoning score of 75 (< 1st centile), working memory sore
of 74 (4th centile) and a processing speed score of 56 (< 1st centile).
She has received diagnoses of mild to moderate intellectual disability
although her verbal comprehension score was in the normal range as
above, attention deficit hyperactivity disorder (ADHD) combined type,
and developmental coordination disorder. She has had difficulties with
mood regulation, anger management and anxiety that has been treated
with methylphenidate. At 12 years of age, she was in 6th grade and had
strengths in reading and writing. She tested at average and below
average for the state standards. She was diagnosed with dyscalculia and
had difficulty with focusing, telling the time and understanding money.
A tight frenulum, narrow palate and difficulties with articulation were
noted in early childhood and a tonsillectomy and adenoidectomy were
performed for sleep apnea and snoring. She continues to have encopr-
esis several times per week. She has not had menstrual periods. In the
family, her oldest brother showed signs of depression at 17 years of age
and a maternal aunt was diagnosed with bipolar disorder. Ethnicity was
European Caucasian for both parents and there was no known con-
sanguinity. On examination, she was conversant with hesitant speech.
Her height was 165 cm (92nd centile) and weight was 42.4 kg (41st
2
European Journal of Medical Genetics 63 (2020) 103850
centile). OFC was 54.2 cm (75–90th centile). She had a short columella,
open mouth and a high arched palate. There was arachnodactyly of her
thumbs, fingers and toes and right 3rd finger measured 8.5 cm (> 97th
centile). She had mild elbow contractures. She had mild hypotonia, but
there were no other neurological signs.
2.3. Patient 3
Patient 3 was a 5-year-old boy who was non-verbal. He was diag-
nosed with severe autism spectrum disorder following loss of words and
regression between the ages of two and three years. He was born pre-
maturely at 29.5 weeks of gestation and remained in the neonatal in-
tensive care unit for six weeks. He was not dysmorphic and had normal
growth parameters. He had a normal 24 h electroencephalogram (EEG)
that was performed due to concerns regarding regression. A brain MRI
scan showed no structural malformations.
2.4. Patient 4
Patient 4 was born at 30 weeks gestation to a 34 year old, G4P2Ab2
mother. Birthweight was 1,265 g (10–25th centile). He had unilateral,
left-sided complete cleft lip and palate that was repaired without
complications. A cranial ultrasound scan showed grade 1 in-
traventricular hemorrhage, but was otherwise normal. He remained in
the neonatal intensive care unit for 41 days and was followed regularly
in the high risk infants clinic after discharge. Developmental delays
were noted in his second year of life and he was evaluated in genetics
clinic at 3 years of age. He had a prominent forehead and flattening of
the midface associated with his clefting, but his examination was
otherwise normal. A karyotype and array comparative genomic hy-
bridizarion were normal. He was admitted for suspected seizure like
activity, but an EEG, including extended video monitoring, showed no
epileptic pattern. He was last seen at four years of age. Growth para-
meters were in the normal range and his facial features were un-
changed. Motor skills were normal, but he continued to have mild
speech and language delays and was receiving speech therapy, physical
therapy and occupational therapy.
2.5. Patient 5
Patient 5 was a male who was delivered at 39 weeks gestation.
Birthweight was 4,167 g (99th centile) and length was 53 cm (95th
centile). Significant hypotonia was noted after birth and he was diag-
nosed with dilated cardiomyopathy. He had a Berlin ventricular assist
device prior to transplant. During the time he had the Berlin, he de-
veloped a clot with emboli and subsequently suffered strokes. He had
had seizures around the time of his strokes and was started on an an-
ticonvulsant. He underwent heart transplantation at 3 months of age.
Brain MRI at age 2 years revealed chronic infarctions in both cerebral
hemispheres, including in the left parietal lobe, left temporal occipital
region, and right frontal lobe. EEG at age 2 years was abnormal, but
considered referable to the known history of bihemispheric stroke. He
had hypotonia, hypermobility, and gross motor delay. He walked at 2.5
years and talked at 2 years. At 6 years of age he had to crawl up stairs,
could not jump, was unable to pedal a tricycle, and had an atypical
walk and run. The child has not had IQ testing, but he does carry a
diagnosis of ADHD. At the time of diagnosis, he was in kindergarten and
received physical therapy and occupational therapy. On physical exam,
no dysmorphic features were noted. He had short stature, decreased
muscle tone, joint hypermobility, pronation of the feet, and a wide-
based gait. He had a chronic history of feeding difficulties and at age 6
was on nasojejunal feedings.
2.6. Patient 6
Patient 6 was a female born at 38 weeks of gestation. Her mother
A. Slavotinek, et al. European Journal of Medical Genetics 63 (2020) 103850

Table 1
Clinical features of patients with JMJD1C variants.
Patient 1 2 3 4 5 6 7

Sex/Age at reporting M/11 y 11 m F/12 y M/5 y M/4 y M/6 y F/4 y F/2 y

Gestation 40 w 39 w 29.5 w 30 w 39 w 38 w 36 w
Birth parameters
Weight 3,750g (50–75th) 3,005g NA 1,265g (10–25th) 4,167g (90–97th) NA 2,400g
(10–25th) (10–25th)
Length 56 cm (> 97th) NA NA NA 53 cm NA NA
Neonatal period Gastroesophageal Left cleft lip/palate; Dilated cardiomyopathy; strokes
reflux Intraventric-ular secondary to treatment; seizures
hemorrhage secondary to strokes
Development
Age at walking 2y 18 m NA NA 2.5 y 14 m -
Age at first words 2.5 y 6y NA NA 2y 18 m -
Neurocognitive
Developmental delays + + + +
ADD/ADHDa + + +
Autism + - + -
Seizures + +
Hypotonia + + +
Growth parameters
Height 158 cm (+0.42 SD) 165 cm NA NA 103 cm (0.2nd) NA 80.5 cm (3rd)
(92nd)
Weight 37 kg (−1.8 SD) 42.4 kg (41st) NA NA 21.6 kg (50th) NA 10.1 kg (2nd)
Head circumference 55 cm (+0.53 SD) 54.2 cm NA NA 51.4 cm (46th) NA NA
(75–90th)
Dysmorphic features
Prominent forehead + +
Flat midface +
Short columella +
Open mouth +
Narrow palate +
Musculoskeletal
Arachnodactyly +
Elbow contractures +
Other
Strabismus +
Investigations
MRIb brain Not done Not done Normal Not done Infarctions (due to Berlin heart), Not done Normal
EEGc Not done Not done Normal Normal Abnormal (secondary to bihemispheric Epileptic Epileptic
stroke) discharges discharges

Y = years; m = months; w = weeks; NA = not available. ADD/ADHDa = attention deficit hyperactivity disorder; MRIb = magnetic resonance imaging;
EEGc = electroencephalogram.

reportedly suffered from epileptic seizures in early childhood, but was
not treated with medications. The child had normal developmental
milestones, with independent walking at 14 months of age and first
words at 18 months of age. Her speech development was delayed and
she received speech therapy and went to a mainstream kindergarden. At
4 years of age, she presented with nocturnal, generalized tonic-clonic
seizures. An EEG showed centro-temporal epileptic discharges. Therapy
with sulthiame was commenced but did not completely control the
seizures.
2.7. Patient 7
Patient 7 was a 2 year old female who presented with seizures at 4
months of age. She has been diagnosed with intractable epilepsy of
unknown etiology. An EEG at 8 months of age showed non-specific left
temporal slowing and multifocal epileptiform discharges.
Electrographic seizures were recorded occasionally with clinical ac-
companiment and were characterized by generalized polyspike and
wave activity followed by generalized decrement. A follow up EEG at
13 months of age showed bitemporal slowing, bitemporal and biocci-
pital synchronous and independent epileptiform discharges. A brain
MRI at 4 months of age showed no abnormalities. A follow up MRI at 21
months also showed no structural abnormalities.
She has exhibited significant developmental delays. From a gross
motor standpoint, she sat independently at 2.5 years of age. She cannot
stand without support and was not taking independent steps. From a
fine motor perspective, she could reach for objects and transfer them
between her hands. She had developed a pincer grasp. From a speech
and language standpoint, she had no words at 2.5 years of age. She had
generalized hypotonia that was symmetrical. At two years of age, she
began developing laughing spells and started biting her feet and toes
and other people.
3. Materials and methods
Exome sequencing was performed with a trio approach on probands
and both biological parents for all patients. All sequence variants are
described with reference to JMJD1C transcripts NM_032776.2/
NM_001322252. Exome capture for Patient 1 was done using the
SeqCap EZ Exome Probes v3.0 (Roche Sequencing, Pleasanton, USA).
Exome libraries were sequenced on an Illumina HiSeq instrument
(Illumina, San Diego, USA) with 151bp paired-end reads at a median
coverage of 100x. Sequence reads were aligned to the hg19 reference
genome using BWA Variants were subsequently called by the GATK
unified genotyper, and annotated using a custom diagnostic annotation
pipeline. A de novo approach was applied for candidate gene identifi-
cation. For patients 2, 3, 4, 5 and 7 who underwent WES as a clinical
test, sequencing technology and the variant interpretation protocol
have been previously reported (Tanaka et al., 2015). Bi-directional se-
quence reads were assembled and aligned to reference sequences based
on NCBI RefSeq transcripts and human genome build GRCh37/UCSC
hg19. Using a custom-developed analysis tool (XomeAnalyzer), data

3
A. Slavotinek, et al. European Journal of Medical Genetics 63 (2020) 103850

Table 2
Sequence variants in JMJD1C gene in patients with developmental delays.
Gene Nucleotide Amino acid Zygos-ity Inherit-ance Mosaicism PolyPhen-2 Mutat-ion ExAC gnomAD Conser-
Alteration Alteration Tas-ter browser/1000 Vation*
genomes

Patient 1
JMJD1C; c.5072A > G p.(Asn1691Ser) Het. de novo - B; 0 DC; p = 1 - 1/30,978; Pt, Mm, Gg,
NM_001322252.1 3.228e-5 Xt
Patient 2
JMJD1C; c.3167_3207 p.(Ser1056Cysfs*10) Het. de novo Y NA DC; p = 1 - - NA
NM_001322252.1 del41
Patient 3
JMJD1C; c.5863-6T > G NA Het. de novo Y NA DC; p = 1 - - NA
NM_001322252.1
Patient 4
JMJD1C; c.1082_1098 p.(Lys361Thrfs*4) Het. de novo - NA DC; p = 1 - - NA
NM_001322252.1 del17
Patient 5
JMJD1C; c.1100T > C p.(Leu367Pro) Het. de novo - PD; 0.983 DC; p = 0.999 - 3/267030; Pt, Mm,
NM_032776.2 1.123e-5 Mmus, Gg,
Dr, Xt
Patient 6
JMJD1C c.349G > A p.(Val117Ile) Het. de novo - B; 0.012 DC; p = 0.983 - - Pt, Mm,
NM_032776.2 Mmus, Gg,
Dr
Patient 7
JMJD1C c.326delC p.(Pro109Leufs*3) Het. Not known - NA DC; p = 1 - - Pt, Mm,
NM_032776.2 Mmus, Gg,
Dr

Conservation* = amino acid residue conservation in different species as determined from MutationTaster: Pt = Pan troglodytes; Mm = Macacca mulatta;
Mmus = Mus musculus; Gg = Gallus gallus; Tr = Takifugu rubripes; Dr = Dario rerio; Xt = Xenopus tropicalis; Het. = heterozygosity; B = benign; DC = disease
causing; NA = not applicable; PD = probably damaging.

were filtered and analyzed to identify sequence variants and most de-
letions and duplications involving three or more coding exons (Retterer
et al., 2015). Reported clinically significant variants were confirmed by
an appropriate orthogonal method in the proband. Sequence and copy
number variants were reported according to the Human Genome Var-
iation Society (HGVS) or International System for Human Cytogenetic
Nomenclature (ISCN) guidelines, respectively. Reportable variants in-
clude pathogenic variants, likely pathogenic variants and variants of
uncertain significance. Likely benign and benign variants, if present,
were not routinely reported. For Patient 6, WES was performed as a trio
with her biological parents at the Institute of Clinical Molecular Biology
at the University of Kiel and the Cologne Center for Genenomics
(https://varbank.ccg.uni-koeln.de) using the Nextera Rapid Capture
Expanded Exome Kit and the Illumina HiSeq2500. The data were ana-
lyzed with a standardized pipeline as reported previously (Helbig et al.,
2019).
4. Results
A summary of the clinical features of these seven patients is pro-
vided in Table 1. The variants in JMJD1C are shown in Table 2 and are
not redescribed in the text. In Patient 2, a heterozygous, de novo variant,
c.833delC, predicted to result in p.(Pro278Leufs*102), was also iden-
tified in the SRCAP gene. This variant has not been seen in public da-
tabases and was also predicted to be pathogenic by the reporting la-
boratory. Nonsense or frameshift variants that result in the formation of
a C-terminal-truncated SRCAP protein miss critical functional domains
and act as dominant negative mutations that cause Floating Harbor
syndrome (Messina et al., 2016). However, this patient did not have
short stature or the facial differences that are typically found in children
with FHS. Patient 4 also had a missense variant in CACNA1A,
c.5666A > G, predicting p.(Asn1889Ser) that was paternally inherited
and classified as a variant of unknown significance. Patient 5 had a
second, likely pathogenic variant that was identified in TTN, c.62426-
2A > C, that was maternally inherited. This TTN variant is believed to
be the cause for the child's cardiomyopathy and may be contributing to
the hypotonia. Patient 6 carried an additional, heterozygous de novo
variant in WDR59, c.896A > G, predicting p.(Asp299Gly), that could
also be relevant to the seizures and speech delay. Lastly, Patient 7 had
2% heteroplasmy for the m.10197G > A variant, predicting p.
(Ala47Thr) in the MT-ND3 gene that was predicted to probably da-
maging with MutationTaster (p = 0.999). However, the degree of
heteroplasmy was considered to be to low to account for the patient's
neurocognitive status.
5. Discussion
Herein we report seven patients with de novo, heterozygous variants
in JMJD1C, comprising three missense variants [c.5072A > G, pre-
dicting p.(Asn1691Ser), c.1100T > C, predicting p.(Leu367Pro) and
c.349G > A, predicting p.(Val117Ile)], two frameshift variants
[c.1082_1098del17, predicting p.(Lys361Thrfs*4) and c.326_326delC,
predicting p.(Pro109Leufs*3)], mosaicism for a frameshift variant
[c.3167_3207del41, predicting p.(Ser1056Cysfs*10)] and mosaicism
for an intronic variant [c.5863-6T > G], that was predicted to disrupt
splicing. All patients shared neurocognitive phenotypes with develop-
mental delays. Three patients had attention deficit disorders, two had
autism spectrum disorder and two patients suffered from seizures.
There were no complications in pregnancy or at the birth. Growth
parameters were normal and dysmorphic features were mild or absent.
There was no individual with a Rett syndrome-like phenotype or autism
spectrum disorder as previously described (Neale et al., 2012; Iossifov
et al., 2014; Sáez et al., 2016) and all of the patients appeared to have
non-specific, neurocognitive differences.
All of the variants in JMJD1C were shown to be de novo, with the
exception of Patient 7, in whom parents were unavailable for testing.
The de novo nature of the variant with confirmed paternity and ma-
ternity from exome sequencing constitutes strong evidence for patho-
genicity (PS2; Richards et al., 2015). In addition, all of the variants
were absent from control databases that constitutes moderate evidence
for pathogenicity (PM2; Richards et al., 2015) except for the missense
variants in Patient 5. All of the variants were predicted to be disease

4
A. Slavotinek, et al.
causing by MutationTaster (Schwarz et al., 2014) and the missense
variants were highly conserved (Table 2) with the exception of the
variant in Patient 1, consistent with the criteria for multiple lines of
computational evidence that support a deleterious effect on the gene/
gene product that constitutes supportive evidence for pathogenicity
(PP3; Richards et al., 2015). Patient 3 had mosaicism for a de novo,
intronic variant in JMJD1C, c.5863-6T > G in intron 15. This variant
was predicted to alter the wildtype donor site to most probably affect
splicing (Human Splicing Finder), although variants affecting the same
splice site, c.5863-3T > C and c.5863-4G > A, have been found in
12/275676 and 4/244,612 individuals in gnomAD.
JMJD1C is under strong constraint for loss of function variants, with
107.7 such variants predicted and only 3 observed (pLI = 1.0;
gnomAD). It is possible that the loss of function variants will prove to be
more pathogenic than missense variants in this gene, but there are too
few patients for analysis at present. Although JMJD1C variants have
previously been associated with intellectual disability, genetic factors in
addition to the JMJD1C variant may be important in the pathogenesis
of the neurocognitive phenotype. Two patients had additional variants
in genes known to be associated with intellectual disabililty, including
SRCAP (Messina et al., 2016) and CACNA1A (Reinson et al., 2016).
Somatic mosaicism was present for two variants (Table 2). For two
patients, the nucleotide substitution has been found as a heterozygous
variant in gnomAD (Table 2). One of the patients also had a likely
pathogenic variant in TTN, a gene associated with cardiomyopathy
and/or skeletal muscle myopathy and another had a variant in WDR59
that was considered a more likely explanation of the phenotype. The
last patient was heteroplasmic for a pathogenic mitochondrial variant.
JMJD1C was first studied as TRIP8, a member of the TRIP1 to
TRIP15 family of genes that encode thyroid hormone receptor beta (TR
beta)-binding proteins (Katoh and Katoh, 2003). The gene has 26 exons
that encode a 2,540 amino acid protein with two bipartite nuclear lo-
calization signals (codons 352-368 and 2,365–2,381), a TRI8H1 domain
(codon 1,697–1,873), TRI8H2 domain (codon 2,057–2,351) and a
JMJC domain (codon 2,387–2,486; Katoh and Katoh, 2003). As JMJC
domain proteins are implicated in chromatin remodeling, TRIP8 was
predicted to be a transcriptional regulator associated with nuclear
hormone receptors (Katoh and Katoh, 2003). TRIP8 interacts with T3
receptor β in a T3-dependent manner, but could also interact with the
retinoid X receptor (RXR) and other transcription factors, including the
vitamin D receptor, peroxisome proliferation-activated receptor
(PPAR)-α and PPAR-γ and retinoic acid receptor (RAR)-α (Lee et al.,
1995; Yuan et al., 1998).
The first report of disruption of the JMJD1C gene in association with
a phenotype concerned a nine-year old male who was evaluated for
impairment in social and communication skills (Castermans et al.,
2007). His milestones were normal, but early language and social de-
velopment were delayed and he did not develop fantasy or pretend play
and did not socialize with his peers. An assessment showed deficits in
social reciprocity, impairment of non-verbal communication, mild de-
lays in expressive and receptive language and marked impairment in
social perspective taking. He fulfilled the DSM-IV criteria for the di-
agnosis of high-functioning autistic spectrum disorder despite a normal
intelligence quotient (Castermans et al., 2007). This child carried a de
novo, balanced paracentric inversion [46,XY,inv(10)(q11.1;q21.3)], in
which the distal breakpoint interrupted the first intron of JMJD1C and
was predicted to disrupt both the TRIP8a and TRIP8b transcripts, with
possible preservation of an alternative TRIP8c transcript (Castermans
et al., 2007).
Subsequent large-scale sequencing studies on children with autism
spectrum disorders revealed additional heterozygous, de novo variants
in JMJD1C. In a study performing trio exome sequencing on patients
with autism spectrum disorder, one missense variant, p.(Val1070Ile),
and one nonsense variant, p.(Arg69*) in JMJD1C were identified (Neale
et al., 2012; Iossifov et al., 2014). Another study examined 215 patients
presenting with autism spectrum disorder, intellectual disability and
5
European Journal of Medical Genetics 63 (2020) 103850
Rett syndrome without known genetic defects and detected seven nu-
cleotide variants clustering in exon 10 of JMJD1C that were not present
in control databases (Sáez et al., 2016). Two of these variants were
considered to be pathogenic, including a heterozygous, de novo variant,
c.488C > T, predicting p.(Pro163Leu), in a 29 year old female who
was diagnosed with classical Rett syndrome (Sáez et al., 2016). This
patient demonstrated loss of social interaction at 18 months of age and
additional findings of delayed speech development, gait dyspraxia,
hand-washing stereotype, teeth grinding, air swallowing, kyphosco-
liosis and tonic epilepsy (Sáez et al., 2016). Although endogenous
JMJD1C is present in the cytoplasm, mutant p.(Pro163Leu)-JMJD1C
was markedly enriched in nuclear chromatin and was less efficient in
demethylating MDC1, a non-histone target of JMJD1C, compared to
wildtype JMJD1C (Sáez et al., 2016). In addition, an im-
munoprecipitation assay demonstrated an interaction between JMJD1C
and MECP2, with less efficient binding of the JMJD1C-Pro163Leu
mutant protein compared to wildtype JMJD1C, thus potentially ex-
plaining the phenotypic overlap between the patient's phenotype and
Rett syndrome (Sáez et al., 2016). Another heterozygous, de novo var-
iant in JMJD1C, c. 3559A > G, predicting p.(Thr1187Ala) was also
noted in a male patient with intellectual disability, but was not func-
tionally studied.
Deletions including JMJD1C have also been published. A three year
old Japanese female who was unable to sit or to crawl and had no single
words was reported to have a 10.4 Mb deletion at chromosome
10q21.3q22 that spanned 84 RefSeq genes, including CTNNA3 and
JMJD1C (Shimojima et al., 2017). This child had Tetralogy of Fallot,
hypotonia, growth delays and dysmorphic features comprising hy-
pertelorism, downslanting palpebral fissures, epicanthal folds, a flat
nasal bridge, low-set ears and a low hairline with a webbed neck and
small hands and feet (Shimojima et al., 2017). However, although
haploinsufficiency for JMJD1C was considered as a possible explana-
tion for the phenotype, numerous other genes were also deleted.
JMJD1C has also been suggested to be a modifier gene for con-
genital heart disease (Guo et al., 2015), as sequencing 184 individuals
with 22q11.2 deletion syndrome for modifying genetic variants re-
vealed ten rare, single nucleotide variants in JMJD1C in nine patients
with congenital heart disease that were not present in controls (Guo
et al., 2015). However, none of these patients reported here demon-
strated cardiac defects.
6. Conclusion
We present seven patients with heterozygous variants in JMJD1C
and neurocognitive differences that included learning delays, ADHD,
autism spectrum disorder and seizures. There were no other consistent
clinical findings. All patients had either mosaicism, a second variant
that could be influencing the intellectual disability, or a variant that
was found in the heterozygous state in a public database. In the lit-
erature, only one JMJD1C variant has undergone functional evaluation.
We conclude that further data strengthening the association of JMJD1C
variants with neurocognitive deficits is needed. Further reports of pa-
tients, functional studies or animal models are still required for a more
definitive implication of JMJD1C in the pathogenesis of intellectual
disability.
CRediT authorship contribution statement
Anne Slavotinek: Conceptualization, Resources, Writing - original
draft, Writing - review & editing. Johanna M. van Hagen: Resources,
Writing - original draft, Writing - review & editing. Louisa Kalsner:
Resources, Writing - original draft, Writing - review & editing.
Shashidhar Pai: Resources, Writing - original draft, Writing - review &
editing. Laura Davis-Keppen: Resources, Writing - original draft,
Writing - review & editing. Lisa Ohden: Resources, Writing - original
draft, Writing - review & editing. Yvonne G. Weber: Resources,
A. Slavotinek, et al.
Writing - original draft, Writing - review & editing. Erica L. Macke:
Resources, Writing - original draft, Writing - review & editing. Eric W.
Klee: Resources. Eva Morava: Resources. Lauren Gunderson:
Resources. Richard Person: Investigation. Shuxi Liu: Investigation.
Marjan Weiss: Resources, Writing - original draft, Writing - review &
editing.
Acknowledgements
We are grateful to the patients and families for their participation.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ejmg.2020.103850.
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