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By Deborah Levenson
Researcher characterizes clinical disease in detail
rare disorder resulting in a skeletal
dysplasia called multicentric osteolysis
nodulosis and arthropathy (MONA) is
the focus of the paper that has won the
American Journal of Medical Genetics’ 2017
John M. Opitz Young Investigator Award.
Given annually since 2002, the award
recognizes clinical research, rather than
molecular studies, conducted by an
investigator who is younger than 40 years
of age or is older and has completed
doctoral training within the past 10 years.
The award honors Dr. Opitz, the journal’s
founding Editor in Chief and one of the
first physicians to recognize and correlate
specific groupings of pediatric anomalies
with heredity.
In her winning paper, Gandham
SriLakshmi Bhavani, PhD, characterizes
in detail the clinical characteristics and
natural history of MONA, which is
also called Torg-Winchester syndrome
(Bhavani, 2017). Dr. Bhavani received
her PhD in October 2017 and is a Senior
Research Fellow in the Department of
Medical Genetics at Kasturba Medical
College at Manipal University in
Karnataka, India.
Dr. Bhavani’s paper reports on
the largest series of individuals with
MONA investigated thus far. “Since
there are only a few publications on
this condition, this work will help in
studying this condition in detail,” states
a recommendation by Dr. Bhavani’s
mentor, Katta M. Girisha, MD, who is
Professor and Head of the Department
of Medical Genetics at Kasturba Medical
College at Manipal University as well as
senior author of the paper.
About MONA and the Study
MONA affects bone and cartilage growth
and is extremely rare. Only 42 affected
individuals, including those described in
Dr. Bhavani’s paper, have been reported.
MONA involves degeneration of bone
tissue and inflammation of the joints. An
autosomal recessive disorder, it is caused
by pathogenic variants of MMP2. Those
variants were discovered in 2001.
As a fellow, Dr. Bhavani worked on
cases of several individuals with various
skeletal disorders including MONA,
and this stimulated her interest in the
condition. She knew that she could recruit
a relatively large number of children with
MONA to her study because India is one
of the world’s most populous countries.
Dr. Bhavani’s literature search identified
30 individuals with MONA, to which
she added 13 more diagnosed by PCR
and Sanger sequencing. “We were able to
gather the largest number of patients with
MONA in the world, and that offered us
the opportunity to describe its natural
history in detail,” she says.
Dr. Bhavani found 8 pathogenic
homozygous mutations, including 5
novel ones, in 11 families. Of the novel
mutations, 2 were deletions that result in
a frame shift likely to cause the formation
of a truncated protein. Two of the
mutations were nonsense variants, and 1
was a missense variant.
The paper describes in detail how
MONA generally progresses. Most
children with MONA appear normal
at birth. Symptoms of the disease
appear in early childhood with signs
of inflammation that include joint
pain, contractures, and swelling of the
hands and feet or joint laxity due to
lysis of bones underlying the hands
and feet. Later stages of the disease
bring coarsening facial features and
overgrowth of the gums. Most children
also develop increasing numbers of firm
Gandham SriLakshmi Bhavani, PhD, is the
recipient of this year’s AJMG John M. Opitz Young
Investigator Award recognizing excellence in
clinical research.
and palpable nodules under the skin.
Sometimes children also have cardiac
anomalies including septal defects or
valve prolapse. Children with MONA
do not get fevers, and they usually lack
biochemical markers of inflammation,
the paper shows. Older children suffer
from osteoporosis or reduced bone mass
in the entire skeletal system.
The study also offers a detailed
overview of the disease’s radiographic
characteristics, including characteristic
lysis of the carpal and tarsal bones,
which often extends to other hand and
foot bones. The radiographs show the
defective bone size and shape that cause
bones to appear broad and irregular.
Because MONA is so rare, a detailed
clinical observation in a larger series
© 2017 Wiley Periodicals, Inc.
of individuals is very important, says
Dr. Bhavani. “It is like in many other
disorders,” she notes. “Once you are
familiar with the condition, it is easy to
“This award is a great honor for me. It is like
a dream come true.”
— Gandham SriLakshmi Bhavani, PhD
Tough Competition
The committee charged with selecting the
award-winning paper received a larger pool
of applicants than it had in previous years.
At least 5 other papers were good enough
to win, says the committee’s chair, Raoul
C.M. Hennekam, MD, PhD, Professor of
Pediatrics and Translational Genetics at the
University of Amsterdam in the Netherlands.
The committee’s unanimous decision was
based on “the smaller points, like the way
the study was set up, the detailedness of the
descriptions, the wording, [and] the quality
of the figures,” he notes.
Dr. Bhavani credits her lauded paper
in part to her mentor, Dr. Girisha, an
expert in skeletal dysplasia. She also
acknowledges the support of her coauthors on this award-winning work.
“In studying rare genetic disorders,
collaborations are essential. You need the
help of many colleagues because you need
a large number of affected individuals for a
meaningful study,” she says. “This award is
a great honor for me. It is like a dream come
true.” She also acknowledges that this is just
the beginning, as the accomplishments of
previous Opitz award winners “have set a
high goal for my career,” she says. “I want
to work hard to reach it.”
Bhavani GS, Shah H, Shukla A, Gupta N,
Gowrishankar K, Rao AP, Kabra M, Agarwal M,
Ranganath P, Ekbote AV, Phadke SR, Kamath A,
Dalal A, Girisha KM. 2016. Clinical and mutation
profile of multicentric osteolysis nodulosis and
arthropathy. Am J Med Genet A 170A(2):410–417.
DOI: 10.1002/ajmg.a.38509
2017 Wiley Periodicals, Inc.
Statement says to hold off on clinical use but supports in vitro research
ultiple genetics organizations are
recommending against current use of
genome editing that culminates in human
pregnancy but are calling for public
funding of genome-editing research done
outside living organisms, with proper
consent and oversight.
Published August 3 in The American
Journal of Human Genetics, the
organizations’ statement focuses on
the CRISPR-Cas9 system (CRISPR), a
genome-editing tool introduced in 2013.
Widely used in genetics research because
it is easily customized and effective on
various cell types and species, CRISPR
is now a valuable tool in research of
germline and somatic cells.
The organizations that issued the
statement are the American Society of
Human Genetics, the Association of Genetic
Nurses and Counsellors, the Canadian
Association of Genetic Counsellors, the
International Genetic Epidemiology
Society, and the National Society of Genetic
Counselors. Organizations that endorsed
the statement include the American
Society for Reproductive Medicine, the
Asia Pacific Society of Human Genetics, the
British Society for Genetic Medicine, the
Human Genetics Society of Australasia, the
Professional Society of Genetic Counselors
in Asia, and the Southern African Society
for Human Genetics.
The statement lays out necessary steps
to be taken before use of genome editing in
clinical applications and pregnancy. These
include establishing compelling medical
rationale, an evidence base supporting its
use, ethical justification, and a transparent
and public process to solicit and incorporate
stakeholder input (Ormond et al, 2017).
Earlier this year, the American College
of Medical Genetics and Genomics and the
National Academy of Sciences took similar
stances on clinical use of germline genome
editing, notes the statement’s first author,
Kelly E. Ormond, MS, CGC, a Professor
in the Department of Genetics and CoDirector of the Master’s Program in
Human Genetics and Genetic Counseling
at Stanford University. “Everyone agrees.
Germline genome editing in the clinical
area is premature,” she says.
The Statement
The workgroup that wrote the statement
convened in 2015 after issuance of the
first published report of germline genome
editing to correct the gene responsible for
beta thalassemia (Liang et al, 2015), notes
Ormond. Coincidentally, the statement
came out one day after the release of a
paper that detailed use of CRISPR in
1-cell embryos to correct pathogenic
MYBPC3 variants that cause hypertrophic
cardiomyopathy (Ma et al, 2017).
Clinical genome editing isn’t yet
appropriate “given the safety and ethical
concerns,” says Paula Amato, MD,
Associate Professor in the Department
of Obstetrics and Gynecology at Oregon
Health & Science University in Portland
and one of the senior authors of the paper
that detailed correction of the MYBPC3
variants (Ma et al, 2017). Although
multiple reports have noted potential
unintended DNA damage induced by
© science photo /
The recent statement calls for:
• Stringent monitoring of the
effect of unwanted mutations and
unintended effects from on-target
edits. “You may not get enough
medical integration [of edits], or they
could end up in another gene and
create another problem,” Ormond
notes. “This is a problem with
somatic and germline editing.” The
statement notes a lack of consensus
on how to do this or what might
constitute an acceptable maximum
rate of off-target edits.
• Lifting prohibitions on using public
funds for studies of germline editing
on human embryos and gametes
outside of the body. “Without public
funding, you lose the ability to
regulate research,” adds Ormond. The
statement warns that such bans tend
to drive research to countries with
fewer regulations and less oversight.
• Consideration of ethical and social
values related to germline genome
editing. Discussion of risks, benefits,
and alternatives to genome editing
must occur among the medical and
scientific communities, people and
families affected by genetic conditions,
and the public, the statement says.
Ormond notes that although earlier
research from Harvard University and
the Pew Research Center showed that
roughly half of the U.S. public was
opposed to genome editing, a more
recent 2017 study finds that twothirds of 1,600 survey respondents
consider genome editing of either
germline or somatic cells generally
acceptable (Scheufele et al, 2017).
Genetics groups are working to reach consensus on genome-editing guidelines.
CRISPR, Dr. Amato’s study did not show
any off-target effects using the researchers’
single-guide RNA, she says. The study
used clinical-quality mature eggs, whereas
previously published gene-editing studies
done in China used abnormal embryos
and immature eggs, she points out, adding
“our numbers were larger and we were
able to correct the mutation with greater
efficiency and fewer untoward effects.”
“Off-target mutations are an important
issue to be aware of and minimize,” says
David Valle, MD, Henry J. Knott Professor
and Director of the McKusick-Nathans
Institute of Genetic Medicine at the Johns
Hopkins School of Medicine in Baltimore.
He notes that a recent study has sparked
controversy with a claim that the CRISPRCas9 genome-editing technique is more
error-prone than previously reported
(Schaefer et al, 2017). Meanwhile, some
investigators have taken issue with
methods used in the study, he notes.
Despite the controversy, Dr. Valle says
he expects that researchers will soon
“minimize off-target effects to almost zero.”
Dr. Valle agrees with the statement’s
criteria for proceeding with clinical
germline genome editing but notes that
opposition will remain despite growing
societal acceptance. “Some people object
to any kind of selection of fertilized
eggs without the disease genotype and
leaving other ones with it in the dish,” he
acknowledges, and he urges geneticists
to remain vigilant. “We are in a time
where the application and ramification
of technology is expanding in ways
we cannot conceive. Pay attention to
developments, keep an open mind, and
rigorously evaluate the developments.”
Ormond KE, Morlock DP, Scholes DT, Bombard Y,
Brody LC, Faucett WA, Garrison NA, Hercher L,
Isasi R, Middleton A, Musunuru K, Shriner D, Virani
A, Young CE. 2017. Human germline genome
editing. Am J Hum Genet 101(2):167–176.
Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z,
Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang
Z, Ma W, Zhou C, Huang J. 2015. CRISPR/Cas9mediated gene editing in human tripronuclear
zygotes. Protein Cell 6(5):363–372.
Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y,
Suzuki K, Koski A, Ji D, Hayama T, Ahmed R, Darby
H, Van Dyken C, Li Y, Kang E, Park AR, Kim D, Kim
ST, Gong J, Gu Y, Xu X, Battaglia D, Krieg SA,
Lee DM, Wu DH, Wolf DP, Heitner SB, Belmonte
JCI, Amato P, Kim JS, Kaul S, Mitalipov S. 2017.
Correction of a pathogenic gene mutation in
human embryos. Nature 548(7668):413–419.
Schaefer KA, Wu WH, Colgan DF, Tsang SH, Bassuk
AG, Mahajan VB. Unexpected mutations after
CRISPR–Cas9 editing in vivo. 2017. Nat Methods
Scheufele DA, Xenos MA, Howell EL, Rose KM, Brossard
D, Hardy BW. 2017. U.S. attitudes on human genome
editing. Science 357(6351):553–554.
DOI: 10.1002/ajmg.a.38510
2017 Wiley Periodicals, Inc.
Data from Roosenboom et al (p. 2886, DOI: 10.1002/ajmg.a. 38471) support the premise that
altered facial shape is a phenotypic marker for nonsyndromic orofacial cleft (OFC) susceptibility.
OFCs are complex traits with wide phenotypic variability and multifactorial inheritance.
Previous research has shown subtle differences between faces of affected children and those of
unaffected relatives compared to control families. These differences imply that variation among
unaffected relatives may be an incomplete expression of an underlying genetic predisposition.
To test this idea, researchers used 3D surface imaging and spatially dense morphometry to
compare facial shape in a sample of 44 unaffected co-twins, plus 241 unaffected age- and sexmatched controls. The researchers studied twins because they share 50% to 100% of genetic risk
factors with affected twin siblings, depending on whether the pairs are monozygotic or dizygotic.
The unaffected co-twins showed statistically significant differences in the midface, lateral upper
face, and forehead regions compared to controls. Co-twins had a distinct pattern of midfacial
retrusion, broader upper faces, and greater protrusion of the mandible and brow ridges. This same
general facial pattern was shown in both unaffected monozygotic and dizygotic co-twin subsets.
The researchers say their results lend credence to the notion that altered facial shape can indeed
be considered a phenotypic marker for OFC risk. The findings also expand the range of what may
be considered part of the OFC phenotypic spectrum, further blurring the boundaries between
affected and unaffected, the researchers say.
typical children. The researchers also expected
stronger, more distinct patterns of variance
between age-matched children with DS and
unrelated typical controls.
To test this hypothesis, the researchers
used 3-dimensional (3D) photogrammatic
images, 3D coordinate locations of 20
anatomical landmarks, and Euclidean Distance
Matrix Analysis methods in 55 children with
DS and 2 control populations. These included
siblings and age-matched typical controls.
Approximately 36% of measurements
differed significantly between children
with DS and sibling samples, whereas
46% differed significantly between
children with DS and unrelated typical
control samples. Nearly 14% of
measurements differed significantly
in variance between children with DS
and DS sibling samples, and 18% of
measurements differed significantly in
variance between children with DS and
unrelated typical control samples.
Of those measures that showed a
significant difference in variance, all were
relatively increased in the sample of DS
These observations have implications
choosing comparison groups when
Figure 1. Facial form differences between Down syndrome
potentially heritable phenotypic
(DS), DS sibling (DSsib), and unrelated euploid (EU) samples.
measures, the researchers say.
Faces of children with Down syndrome (DS) are
more like typical siblings’ faces than those of
unrelated typical individuals, write Starbuck et
al (p. 2861, DOI: 10.1002/ajmg.a. 38464).
Most studies assessing DS facial
characteristics involve comparing and contrasting
individuals with DS to unrelated typical
individuals. This process confounds differences
from shared or unshared background genes with
differences caused by DS, say researchers.
They hypothesized that faces of age-matched
children with DS and their siblings would exhibit
fewer significant form and variance differences
relative to the faces of age-matched unrelated
DOI: 10.1002/ajmg.a.37925
2017 Wiley Periodicals, Inc.
Keppler-Noreuil et al (p. 2873,
DOI: 10.1002/ajmg.a. 38469) present
some of the first insights into
potential differing etiologies for
cloacal exstrophy (CE) and persistent
cloaca (PC).
The term “cloaca” refers to
malformation involving fusion of the
rectum with the vagina or urethra
into a single common channel.
Studies of cloacal defects’
characteristics and risk factors often
examine CE and PC together rather
than investigating the possibility that
they may have different etiologies.
For this reason, the researchers
enumerated clinical features for 47
children with CE and 54 children
with PC who participated in the
National Birth Defects Prevention
Study. Thirty-three CE cases were
classified as isolated and 14 as
multiple, meaning patients had
other unassociated major defects.
The researchers also compared these
affected children’s and their mothers’
characteristics to those of 11,829
unaffected controls using chi-square
or Fisher’s exact tests.
Cloacal defects grouped as CE
or PC had similar and overlapping
kidney, urinary, gastrointestinal,
and skeletal and spinal defects.
The most frequently associated
defects with both multiple CE and
PC were congenital heart defects.
Many more females than males had
cloacal defects.
CE and PC do have distinguishing characteristics, the researchers
note. Isolated CE occurred more
frequently than isolated PC. Isolated
PC was more likely to have other
multiple unassociated defects.
Risk-factor analysis revealed
statistically significant positive
associations for both PC and
CE with reported maternal use
of any fertility medication or
assisted reproductive technology,
periconceptional exposure to
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