Publications by authors named "Judith G Hall"

93 Publications

The mystery of monozygotic twinning II: What can monozygotic twinning tell us about Amyoplasia from a review of the various mechanisms and types of monozygotic twinning?

Authors:
Judith G Hall

Am J Med Genet A 2021 Mar 25. Epub 2021 Mar 25.

University of British Columbia and Children's and Women's Health Centre of British Columbia, Department of Pediatrics and Medical Genetics, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.

Monozygotic (MZ) twins ("identical twins") are essentially unique to human beings. Why and how they arise is not known. This article reviews the possible different types of MZ twinning recognized in the previous article on twins and arthrogryposis. There appear to be at least three subgroups of MZ twinning: spontaneous, familial, and those related to artificial reproductive technologies. Each is likely to have different etiologies and different secondary findings. Spontaneous MZ twinning may relate to "overripe ova." Amyoplasia, a specific nongenetic form of arthrogryposis, appears to occur in spontaneous MZ twinning and may be related to twin-twin transfusion.
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http://dx.doi.org/10.1002/ajmg.a.62177DOI Listing
March 2021

The mystery of monozygotic twinning I: What can Amyoplasia tell us about monozygotic twinning and the possible role of twin-twin transfusion?

Authors:
Judith G Hall

Am J Med Genet A 2021 Mar 24. Epub 2021 Mar 24.

Department of Pediatrics and Medical Genetics, British Columbia Children's Hospital, University of British Columbia and Children's and Women's Health Centre of British Columbia, Vancouver, Canada.

Amyoplasia is a very specific, nongenetic clinically recognizable form of arthrogryposis, representing about one-third of individuals with arthrogryposis surviving the newborn period. There is a markedly increased number of individuals with Amyoplasia who are one of monozygotic (MZ) twins, with the other twin being normal. Thus, it would appear that Amyoplasia is definitely associated with and may be caused by an MZ twinning event. The twin-twin transfusion seen in MZ twins could play an etiologic role in producing Amyoplasia. In this article, Amyoplasia twinning is compared to twinning in other forms of arthrogryposis. The accompanying paper examines various types of MZ twinning (Hall, 2021). Amyoplasia is primarily associated with spontaneous MZ twinning.
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http://dx.doi.org/10.1002/ajmg.a.62172DOI Listing
March 2021

Deformations associated with arthrogryposis.

Authors:
Judith G Hall

Am J Med Genet A 2021 Mar 8. Epub 2021 Mar 8.

University of British Columbia and Children's and Women's Health Centre of British Columbia, Department of Pediatrics and Medical Genetics, British Columbia Children's Hospital, Vancouver, British Columbia, USA.

Fetal movement is essential to normal human development. If the fetus does not move for whatever reason, then multiple organs and organ systems develop secondary and tertiary effects not normally present. Most of these are deformations with secondary structural damage.
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http://dx.doi.org/10.1002/ajmg.a.62151DOI Listing
March 2021

Using the Term Amyoplasia Loosely Can Lead to Confusion.

Authors:
Judith G Hall

Am J Hum Genet 2020 12;107(6):1186-1187

Department of Pediatrics and Medical Genetics, British Columbia Children's Hospital, Children's and Women's Health Centre of British Columbia and University of British Columbia, 4500 Oak St., room C234, Vancouver, BC V6H 3N1, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2020.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820618PMC
December 2020

The spectrum of brain malformations and disruptions in twins.

Am J Med Genet A 2020 Nov 18. Epub 2020 Nov 18.

Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.
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http://dx.doi.org/10.1002/ajmg.a.61972DOI Listing
November 2020

Continuing contributions of older academics.

Authors:
Judith G Hall

Am J Med Genet A 2021 02 6;185(2):647-657. Epub 2020 Nov 6.

Professor Emerita, University of British Columbia & Children's and Women's Health Centre of BC, Department of Pediatrics and Medical Genetics, BC's Children's Hospital, Vancouver, British Columbia, Canada.

Academics go through many stages. Perhaps the most challenging is retirement. This article summarizes some of the challenges and opportunities that await. Now that we are all living longer and healthier, it seems a waste of human capital not to utilize the hard-won skills of academia during our later years in new and creative ways. Although health and memory cannot be taken for granted, most older academics continue to evolve, gain wisdom, and make new types of contributions to society.
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http://dx.doi.org/10.1002/ajmg.a.61946DOI Listing
February 2021

Recurrent constellations of embryonic malformations re-conceptualized as an overlapping group of disorders with shared pathogenesis.

Am J Med Genet A 2020 11 14;182(11):2646-2661. Epub 2020 Sep 14.

Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

Several recurrent malformation associations affecting the development of the embryo have been described in which a genetic etiology has not been found, including LBWC, MURCS, OAVS, OEIS, POC, VACTERL, referred to here as "recurrent constellations of embryonic malformations" (RCEM). All are characterized by an excess of reported monozygotic discordant twins and lack of familial recurrence. We performed a comprehensive review of published twin data across all six phenotypes to allow a more robust assessment of the association with twinning and potential embryologic timing of a disruptive event. We recorded the type of twinning, any overlapping features of another RCEM, maternal characteristics, and the use of ART. Statistically significant associations included an excess of monozygotic twins and 80% discordance rate for the phenotype across all twins. There was an 18.5% rate of ART and no consistently reported maternal adverse events during pregnancy. We found 24 instances of co-occurrence of two RCEM, suggesting a shared pathogenesis across all RCEM phenotypes. We hypothesize the following timing for RCEM phenotypes from the earliest perturbation in development to the latest: LBWC, POC, OEIS, VACTERL, OAVS, then MURCS. The RCEM group of conditions should be considered a spectrum that could be studied as a group.
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http://dx.doi.org/10.1002/ajmg.a.61847DOI Listing
November 2020

50 Years Ago in TheJournalofPediatrics: Arthrogryposis Multiplex Congenita: A Clinical Investigation.

J Pediatr 2020 02;217:72

Emerita Professor of Pediatrics, University of British Columbia, Vancouver, British Columbia.

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http://dx.doi.org/10.1016/j.jpeds.2019.08.022DOI Listing
February 2020

Collaborating to advance interdisciplinary care for individuals with arthrogryposis.

Am J Med Genet C Semin Med Genet 2019 09 31;181(3):273-276. Epub 2019 Aug 31.

Pediatrics and Medical Genetics, Children's and Women's Health Centre of BC, UBC, Vancouver, British Columbia, Canada.

This Special Issue on Interdisciplinary Care in Arthrogryposis highlights a collection of articles spanning topics in interdisciplinary care, genetic discoveries, and clinical research. An international group of clinicians and researchers from various backgrounds who attended the "3rd International Symposium on Arthrogryposis", held in Philadelphia, September 24-26, 2018, were invited to contribute to this issue. The goal of the 2018 Symposium and of this Special Issue is to provide momentum to advancing evidence-based practice and research in arthrogryposis, by working collaboratively with adults and families of children with arthrogryposis, clinicians, and researchers. The contents of this issue cover a range of topics from defining and classifying arthrogryposis multiplex congenita to early detection, rehabilitation, and orthopedic management, advances in genetic pathways, patient registries, autopsy guidelines, and research findings in the pediatric and adult populations with arthrogryposis. We hope that this issue provides an overview as well as new knowledge on arthrogryposis to generate more conversations at the international level, and advance care and research for individuals with arthrogryposis.
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http://dx.doi.org/10.1002/ajmg.c.31741DOI Listing
September 2019

Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care.

Am J Med Genet C Semin Med Genet 2019 09 13;181(3):345-353. Epub 2019 Aug 13.

Professor Emerita, Department of Pediatrics and Medical Genetics, University of British Columbia, Vancouver, Canada.

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X-linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.
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http://dx.doi.org/10.1002/ajmg.c.31732DOI Listing
September 2019

A standardized autopsy protocol for arthrogryposis (multiple congenital contractures).

Am J Med Genet C Semin Med Genet 2019 09 2;181(3):474-478. Epub 2019 Aug 2.

Department of Medical Genetics and Pediatrics, University of British Columbia; British Columbia Children's Hospital, Child and Family Research Institute, Vancouver, British Columbia, Canada.

Arthrogryposis multiplex congenita (AMC) describes disorders with multiple joint contractures that arise from neurological, neuromuscular, or mechanical origin. Although impaired fetal movement is the typical clinical presentation, the etiology underlying this phenotype for a number of conditions remains unknown. In an effort to better characterize and define the etiologies underlying these disorders, we recommend a standardized autopsy protocol that will allow for appropriate diagnosis and a methodical approach for examination that will facilitate subsequent study by investigators across disciplines. To further support investigation, we have also established an AMC autopsy registry to bank tissue obtained at autopsy for subsequent study.
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http://dx.doi.org/10.1002/ajmg.c.31731DOI Listing
September 2019

Gene ontology analysis of arthrogryposis (multiple congenital contractures).

Am J Med Genet C Semin Med Genet 2019 09 1;181(3):310-326. Epub 2019 Aug 1.

Department of Medical Genetics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.

In 2016, we published an article applying Gene Ontology Analysis to the genes that had been reported to be associated with arthrogryposis (multiple congenital contractures) (Hall & Kiefer, 2016). At that time, 320 genes had been reported to have mutations associated with arthrogryposis. All were associated with decreased fetal movement. These 320 genes were analyzed by biological process and cellular component categories, and yielded 22 distinct groupings. Since that time, another 82 additional genes have been reported, now totaling 402 genes, which when mutated, are associated with arthrogryposis (arthrogryposis multiplex congenita). So, we decided to update the analysis in order to stimulate further research and possible treatment. Now, 29 groupings can be identified, but only 19 groups have more than one gene.
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http://dx.doi.org/10.1002/ajmg.c.31733DOI Listing
September 2019

Research platform for children with arthrogryposis multiplex congenita: Findings from the pilot registry.

Am J Med Genet C Semin Med Genet 2019 09 29;181(3):427-435. Epub 2019 Jul 29.

Shriners Hospital for Children, Montreal, Quebec, Canada.

A pediatric registry for arthrogryposis multiplex congenita (AMC) proposes to advance research by providing the platform to inform the distribution, etiology, and natural history of AMC. The registry was piloted on 40 families of children (mean = 8.25 years, 48% males) presenting with AMC across two hospitals in North America. Data on the child's demographic and newborn variables, mothers' and fathers' demographic variables, lifestyle habits, and medical history were collected using a telephone interview with the primary caregiver and review of medical charts. Mean gestational age was 38 weeks, 97% of children presented with lower extremity deformities, and 74% of neonatal interventions targeted the lower extremity. Newborns spent an average of 14 days in the hospital (range 2-56 days) mostly for diagnostic workup and feeding difficulties. Half (49%) of the sample had internal organ involvement. Genetic testing was done on 48% of the children, including chromosome studies, single gene, whole-exome/genome sequencing, and/or microarray studies. Genetic findings were inconclusive in most. Two-thirds of mothers (67%) reported inconsistently feeling fetal movements. This pilot study contributed to the refinement of participant selection, identification of data source, expansion of data sets, and areas for future exploration prior to the implementation of a multisite AMC pediatric registry.
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http://dx.doi.org/10.1002/ajmg.c.31724DOI Listing
September 2019

Fetal cervical hyperextension in arthrogryposis.

Authors:
Judith G Hall

Am J Med Genet C Semin Med Genet 2019 09 26;181(3):354-362. Epub 2019 Jul 26.

Department of Medical Genetics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.

Perhaps the most dramatic position of a newborn after delivery is when there is hyperextension of the neck and spine. It will have been presented in utero and today, almost always, such babies will have been delivered by C-section. The associated anomalies are variable. The process(es) that can lead to cervical hyperextension is/are largely unknown. The outcome is variable from lethal to completely resolve. Individuals with arthrogryposis and in particular with Amyoplasia appear to have an increased frequency of neck, cervical, and spine hyperextension at birth. We present here 41 cases of arthrogryposis (mainly Amyoplasia) with fetal cervical hyperextension. The outlook is surprisingly good if spinal cord trauma does not occur. Ultrasound late in pregnancy when arthrogryposis is recognized prenatally should determine whether cervical hyperextension has developed, so that appropriate preventive measures can be taken.
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http://dx.doi.org/10.1002/ajmg.c.31727DOI Listing
September 2019

Fetal arthrogryposis: Challenges and perspectives for prenatal detection and management.

Am J Med Genet C Semin Med Genet 2019 09 18;181(3):327-336. Epub 2019 Jul 18.

Department of Medical Genetics and Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.

Antenatal identification of fetuses with multiple congenital contractures or arthrogryposis multiplex congenita (AMC) may be challenging. The first clinical sign is often reduced fetal movement and/or contractures, as seen on prenatal ultrasounds. This can be apparent at any point, from early to late pregnancy, may range from mild to severe involvement, with or without associated other structural anomalies. Possible etiologies and their prognosis need to be interpreted with respect to developmental timing. The etiology of AMC is highly heterogeneous and making the specific diagnosis will guide prognosis, counseling and prenatal and perinatal management. Current ultrasound practice identifies only approximately 25% of individuals with arthrogryposis prenatally before 24 weeks of pregnancy in a general obstetrics care population. There are currently no studies and guidelines that address the question of when and how to assess for fetal contractures and movements during pregnancy. The failure to identify fetuses with arthrogryposis before 24 weeks of pregnancy means that physicians and families are denied reproductive options and interventions that may improve outcome. We review current practice and recommend adjusting the current prenatal imaging and genetic diagnostic strategies to achieve early prenatal detection and etiologic diagnosis. We suggest exploring options for in utero therapy to increase fetal movement for ongoing pregnancies.
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http://dx.doi.org/10.1002/ajmg.c.31723DOI Listing
September 2019

International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita.

Am J Med Genet C Semin Med Genet 2019 09 7;181(3):288-299. Epub 2019 Jul 7.

Department of Pediatrics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent in clinical and research communities. A definition of AMC was recently developed using a modified Delphi consensus method involving 25 experts in the field of AMC from 8 countries. Participants included health care professionals, researchers, and individuals with AMC. An annotation of the definition provides more in-depth explanations of the different sentences of the AMC definition and is useful to complement the proposed definition. The aim of this study was to provide an annotation of the proposed consensus-based AMC definition. For the annotation process, 17 experts in AMC representing 10 disciplines across 7 countries participated. A paragraph was developed for each sentence of the definition using an iterative process involving multiple authors with varied and complementary expertise, ensuring all points of view were taken into consideration. The annotated definition provides an overview of the different topics related to AMC and is intended for all stakeholders, including youth and adults with AMC, their families, and clinicians and researchers, with the hopes of unifying the understanding of AMC in the international community.
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http://dx.doi.org/10.1002/ajmg.c.31721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771513PMC
September 2019

Classification of arthrogryposis.

Am J Med Genet C Semin Med Genet 2019 09 4;181(3):300-303. Epub 2019 Jul 4.

Grenoble Institut des neurosciences, University of Grenoble La Tronche, France.

There is a need for a system to classify various forms of arthrogryposis. None is satisfactory or complete. Nevertheless, several have been developed to meet the needs of clinicians, prenatal diagnosticians, researchers, and basic scientists. They all await more insight into basic mechanisms.
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http://dx.doi.org/10.1002/ajmg.c.31716DOI Listing
September 2019

Aerodigestive and communicative behaviors in anencephalic and hydranencephalic infants.

Birth Defects Res 2019 01 10;111(2):41-52. Epub 2018 Dec 10.

Department of Linguistics, University of British Columbia, Vancouver, Canada.

The aerodigestive and communicative behaviors of anencephalic and hydranencephalic patients are assessed from literature sources and are compared with documented neural structures present in the brainstem, subcortical, and cortical regions of the brain. Much of the data analyzed corroborate previous neurological studies, which focus on central pattern generators and development in model organisms. However, findings suggest that further research is necessary to determine which components of these systems support these behaviors. A low reporting rate of behavior in tandem with pathology is observed throughout the literature. More data pairing behavior and pathology is recommended, both in the interest of understanding the relationship between neural structures and functions, and to provide clinicians with more information about a patient's signs and symptoms. Potential clinical practices are recommended to increase documentation about patients within this population.
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http://dx.doi.org/10.1002/bdr2.1424DOI Listing
January 2019

Genetics and Classifications.

J Pediatr Orthop 2017 Jul/Aug;37 Suppl 1:S4-S8

*Departments of Medical Genetics and Pediatrics, University of British Columbia †British Columbia Children's Hospital, Child and Family Research Institute, Vancouver, BC, Canada ‡Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden §Department of Orthopaedic Surgery, Shriners Hospital for Children, Philadelphia, PA.

Arthrogryposis multiplex congenital (AMC) is a descriptive term for a group of conditions that all share the characteristic of congenital contractures. There are an estimated 400 discrete diagnoses that can lead to a child being born with arthrogryposis. The 2 biggest categories of conditions are amyoplasia and distal arthrogryposis, which combined make up ∼50% to 65% of all diagnoses within the AMC subset. Amyoplasia, the most common AMC condition, seems to be a nongenetic syndrome, leading to very characteristic upper and lower limb contractures. The distal arthrogryposes, in contrast, have an underlying genetic abnormality, which in many cases seems to target the fast twitch muscles of the developing fetus. Classifying AMC is a difficult task, given the broad range of conditions represented. Four different classification schemes are presented.
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http://dx.doi.org/10.1097/BPO.0000000000000997DOI Listing
October 2017

Background to the 2nd International Symposium on Arthrogryposis.

J Pediatr Orthop 2017 Jul/Aug;37 Suppl 1:S2-S3

*Childrens Hand and Upper Limb Service, Birmingham Childrens Hospital, Edgbaston, Birmingham, UK †Department of Pediatrics and Medical Genetics, British Columbia's Children's Hospital and University of British Columbia, Vancouver, BC, Canada ‡Department of Pediatric Orthopaedic Surgery, Karolinska University Hospital, Stockholm, Sweden §Shriners Hospitals for Children-Philadelphia, Philadelphia, PA.

Arthrogryposis multiplex congenital is a relatively uncommon condition, with little consensus on treatment. In 2007, the 1st International Symposium on Arthrogryposis was held in Birmingham, United Kingdom, to bring together patients, their families, and a multinational group of health care experts in the field of arthrogryposis, to discuss various aspects of the care of patients with arthrogryposis multiplex congenital. From that meeting, there was a coalescence of thought on diagnosis and classification, a sharing of practices on treatments and their outcomes, and an agreement on future directions. At the beginning of the 2nd International Symposium on Arthrogryposis held in Saint Petersburg in September 2014, Russia, these "lessons learnt" were synopsized to set the tone for the new meeting.
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http://dx.doi.org/10.1097/BPO.0000000000000996DOI Listing
October 2017

Reflections on an academic career.

Authors:
Judith G Hall

Mol Genet Genomic Med 2017 May 21;5(3):187-195. Epub 2017 May 21.

Departments of Medical Genetics and PediatricsUniversity of British Columbia and BC Children's Hospital VancouverBritish ColumbiaCanada.

There are many undefined aspects to an academic medical career. This article attempts to provide some guidance about things to consider.
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http://dx.doi.org/10.1002/mgg3.298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441417PMC
May 2017

The Clinic Is My Laboratory: Life as a Clinical Geneticist.

Authors:
Judith G Hall

Annu Rev Genomics Hum Genet 2017 08 6;18:1-29. Epub 2017 Mar 6.

Department of Medical Genetics and Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver V6H 3N1, Canada; email:

Clinical genetics is the application of advances in genetics and medicine to real human families. It involves diagnosis, care, and counseling concerning options available to affected individuals and their family members. Advances in medicine and genetics have led to dramatic changes in the scope and responsibilities of clinical genetics. This reflection on the last 50+ years of clinical genetics comes from personal experience, with an emphasis on the important contributions that clinical geneticists have made to the understanding of disease/disorder processes and mechanisms. The genetics clinic is a research laboratory where major advances in knowledge can and have been made.
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http://dx.doi.org/10.1146/annurev-genom-091416-035213DOI Listing
August 2017

Arthrogryposis as a Syndrome: Gene Ontology Analysis.

Mol Syndromol 2016 Jul 7;7(3):101-9. Epub 2016 Jun 7.

Translational Genomics Research Institute (TGen), Phoenix, Ariz., USA.

Arthrogryposis by definition has multiple congenital contractures. All types of arthrogryposis have decreased in utero fetal movement. Because so many things are involved in normal fetal movement, there are many causes and processes that can go awry. In this era of molecular genetics, we have tried to place the known mutated genes seen in genetic forms of arthrogryposis into biological processes or cellular functions as defined by gene ontology. We hope this leads to better identification of all interacting pathways and processes involved in the development of fetal movement in order to improve diagnosis of the genetic forms of arthrogryposis, to lead to the development of molecular therapies, and to help better define the natural history of various types of arthrogryposis.
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http://dx.doi.org/10.1159/000446617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988256PMC
July 2016

Summary of the 2nd International Symposium on Arthrogryposis, St. Petersburg, Russia, September 17-19, 2014.

Am J Med Genet A 2015 Nov 24;167A(11):2866. Epub 2015 Jun 24.

Department of Orthopedic Surgery, Shriners Hospital for Children, Philadephia, Pennsylvania.

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http://dx.doi.org/10.1002/ajmg.a.37219DOI Listing
November 2015

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.

Mol Genet Genomic Med 2015 Jul 8;3(4):283-301. Epub 2015 Apr 8.

Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.

Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.
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http://dx.doi.org/10.1002/mgg3.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521965PMC
July 2015

Summary of the 2nd International Symposium on Arthrogryposis, St. Petersburg, Russia, September 17-19, 2014.

Am J Med Genet A 2015 Jun 5;167(6):1193-5. Epub 2015 Apr 5.

Department of Orthopedic Surgery, Shriners Hospital for Children, Philadephia, Pennsylvania.

Enormous progress has been made in understanding the etiology and therapies for arthrogryposis (multiple congenital contractures). A 2nd International Symposium on Arthrogryposis was sponsored by the Turner Institute in St. Petersburg, Russia. Olga Agranovich, Head of the Arthrogryposis Department of the Turner Institute, organized this special meeting. Care providers from multiple disciplines from all over the world representing 18 nations attended. Participants included: Pediatric orthopedic specialists, rehabilitation physicians, occupational therapists, physical therapists, medical geneticists, neurologists, craniofacial physicians, psychologists, developmental biologists, as well as representatives from parent support groups. The 1st symposium established the need for a collaborative and interdisciplinary approach to the treatment of arthrogryposis, engagement of parent support organizations, and the aim for more research. The Second Symposium highlighted the continuing need for more research on various therapies, identification of different types of arthrogryposis, standardized descriptions of severity, development of new orthotics, improved prenatal diagnosis, and studying adult outcome. Major progress has been made on both upper and lower limb treatments.
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http://dx.doi.org/10.1002/ajmg.a.36938DOI Listing
June 2015

Review of X-linked syndromes with arthrogryposis or early contractures-aid to diagnosis and pathway identification.

Am J Med Genet A 2015 May 19;167A(5):931-73. Epub 2015 Mar 19.

Integrated Functional Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona.

The following is a review of 50 X-linked syndromes and conditions associated with either arthrogryposis or other types of early contractures. These entities are categorized as those with known responsible gene mutations, those which are definitely X-linked, but the responsible gene has not been identified, and those suspected from family history to be X-linked. Several important ontology pathways for known disease genes have been identified and are discussed in relevance to clinical characteristics. Tables are included which help to identify distinguishing clinical features of each of the conditions.
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http://dx.doi.org/10.1002/ajmg.a.36934DOI Listing
May 2015

Pallister-Hall syndrome has gone the way of modern medical genetics.

Authors:
Judith G Hall

Am J Med Genet C Semin Med Genet 2014 Dec 25;166C(4):414-8. Epub 2014 Nov 25.

The Pallister-Hall syndrome (PHS) was identified and described as a specific entity in the late 1970s and early 1980s. Subsequently, many patients were reported expanding the phenotype. Familial cases demonstrated variability and lead to linkage and then gene identification. Mutations in the responsible gene, GLI3 are also known to be involved in several other disorders. Genotype/phenotype correlations have led to fine mapping of GLI3 and the recognition that PHS is caused by dominant negative mutations in the middle third of the gene.
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http://dx.doi.org/10.1002/ajmg.c.31419DOI Listing
December 2014

Oligohydramnios sequence revisited in relationship to arthrogryposis, with distinctive skin changes.

Authors:
Judith G Hall

Am J Med Genet A 2014 Nov 26;164A(11):2775-92. Epub 2014 Aug 26.

Departments of Medical Genetics, Pediatrics, University of British Columbia, BC Children's Hospital Vancouver, British Columbia, Canada.

Thirty cases of arthrogryposis associated with longstanding oligohydramnios were identified among 2,500 cases of arthrogryposis (1.2%) and were reviewed for clinical features and natural history. None had renal agenesis or renal disease. Twenty-two had a history of known rupture of membranes. Only 50% had pulmonary hypoplasia at birth and only two died (7%). Sixty percent (18/30) seemed to have their multiple congenital contractures (MCC) primarily on the basis of compression related to the longstanding oligohydramnios and responded well to physical therapy. On average they did not have intrauterine growth restriction. "Potter" facies and remarkable skin changes were present in all. An excess of males was observed in spite of the lack of genitourinary anomalies.
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http://dx.doi.org/10.1002/ajmg.a.36731DOI Listing
November 2014