Publications by authors named "Helga Toriello"

51 Publications

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

Am J Med Genet C Semin Med Genet 2020 12 4;184(4):1030-1041. Epub 2020 Dec 4.

Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.
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http://dx.doi.org/10.1002/ajmg.c.31871DOI Listing
December 2020

Correction: Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing.

Genet Med 2020 Sep;22(9):1568

Department of Pediatrics/Human Development, Spectrum Health Hospitals and College of Medicine, Michigan State University, Grand Rapids, MI, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0891-5DOI Listing
September 2020

Training the next generation of genomic medicine providers: trends in medical education and national assessment.

Genet Med 2020 10 18;22(10):1718-1722. Epub 2020 Jun 18.

Department of Human Genetics, University of Chicago, Chicago, IL, USA.

Purpose: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®).

Methods: A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline.

Results: The committee identified 13.4%, 10.4%, and 4.4% of Steps 1, 2 and 3 respectively, as having genetics content. The genetics content of the exams became less pertinent to the questions from Step 1 to 3, with decreasing genetics content by exam and increasing percentages of questions identified as having genetics content in the distractors only.

Conclusion: The current distribution of genetics in USMLE licensing examinations reflects traditional curricular approaches with genetics as a basic science course in the early years of medical school and de-emphasizes clinical relevance of the field. These observations support the notion that further integration is required to move genetics into the clinical curriculum of medical schools and the clinical content of USMLE Step exams.
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http://dx.doi.org/10.1038/s41436-020-0855-9DOI Listing
October 2020

Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing.

Genet Med 2020 12 12;22(12):2125. Epub 2020 Jun 12.

Department of Pediatrics/Human Development, Spectrum Health Hospitals and College of Medicine, Michigan State University, Grand Rapids, MI, USA.

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http://dx.doi.org/10.1038/s41436-020-0843-0DOI Listing
December 2020

Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A.

Am J Med Genet A 2016 12 9;170(12):3343-3346. Epub 2016 Sep 9.

Spectrum Health Hospitals, Grand Rapids, Michigan.

Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, is a rare condition with fewer than 40 patients reported in the literature. Characteristic physical findings include neonatal progeroid appearance, sparse scalp hair, prominent scalp veins, and lipoatrophy; in addition, neonatal teeth are often a distinctive finding. The inheritance pattern of this disorder has been postulated to be autosomal recessive, although a specific gene has not been identified. Here we report an infant with the characteristic phenotypic features of Wiedemann-Rautenstrauch syndrome in whom exome sequencing identified two pathogenic variants in POLR3A: c.1909+18G>A; p.(Y637Cfs*23) and c.2617C>T; p.(R873*). Mutations in POLR3A (OMIM #614258) are associated with 4H leukodystrophy syndrome characterized by the triad of hypomyelination, hypodontia, and hypogonadotrophic hypogonadism. The present patient's genotype implies a broader phenotypic range for POLR3A mutations and might expand the clinical spectrum. This proband is notable because she had two null pathogenic variants. Replication in other patients clinically diagnosed with Wiedemann-Rautenstrauch syndrome is needed to further demonstrate this gene-disease association. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37960DOI Listing
December 2016

Update on the Toriello-Carey syndrome.

Am J Med Genet A 2016 10 11;170(10):2551-8. Epub 2016 Aug 11.

Division of Medical Genetics, University of Washington, Seattle, Washington.

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37735DOI Listing
October 2016

Randomized trial finds that prostate cancer genetic risk score feedback targets prostate-specific antigen screening among at-risk men.

Cancer 2016 Nov 19;122(22):3564-3575. Epub 2016 Jul 19.

Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Prostate-specific antigen (PSA) screening may reduce death due to prostate cancer but leads to the overdiagnosis of many cases of indolent cancer. Targeted use of PSA screening may reduce overdiagnosis. Multimarker genomic testing shows promise for risk assessment and could be used to target PSA screening.

Methods: To test whether counseling based on the family history (FH) and counseling based on a genetic risk score (GRS) plus FH would differentially affect subsequent PSA screening at 3 months (primary outcome), a randomized trial of FH versus GRS plus FH was conducted with 700 whites aged 40 to 49 years without prior PSA screening. Secondary outcomes included anxiety, recall, physician discussion at 3 months, and PSA screening at 3 years. Pictographs versus numeric presentations of genetic risk were also evaluated.

Results: At 3 months, no significant differences were observed in the rates of PSA screening between the FH arm (2.1%) and the GRS-FH arm (4.5% with GRS-FH vs. 2.1% with FH: χ = 3.13, P = .077); however, PSA screening rates at 3 months significantly increased with given risk in the GRS-FH arm (P = .013). Similar results were observed for discussions with physicians at 3 months and PSA screening at 3 years. Average anxiety levels decreased after the individual cancer risk was provided (P = .0007), with no differences between groups. Visual presentation by pictographs did not significantly alter comprehension or anxiety.

Conclusions: This is likely the first randomized trial of multimarker genomic testing to report genomic targeting of cancer screening. This study found little evidence of concern about excess anxiety or overuse/underuse of PSA screening when multimarker genetic risks were provided to patients. Cancer 2016;122:3564-3575. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247411PMC
November 2016

2013 Review and Update of the Genetic Counseling Practice Based Competencies by a Task Force of the Accreditation Council for Genetic Counseling.

J Genet Couns 2016 10 23;25(5):868-79. Epub 2016 Jun 23.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

The first practice based competencies (PBCs) for the field of genetic counseling were adopted by the American Board of Genetic Counseling (ABGC), 1996. Since that time, there has been significant growth in established and new work settings (clinical and non-clinical) and changes in service delivery models and the roles of genetic counselors. These changes prompted the ABGC to appoint a PBC Task Force in 2011 to review the PBCs with respect to their current relevance and to revise and update them as necessary. There are four domains in the revised PBCs: (I) Genetics Expertise and Analysis (II) Interpersonal, Psychosocial and Counseling Skills (III) Education and (IV) Professional Development and Practice. There are 22 competencies, each clarified with learning objectives or samples of activities and skills; a glossary is included. New competencies were added that address genomics, genetic testing and genetic counselors' roles in risk assessment, education, supervision, conducting research and presenting research options to patients. With PBCs serving as the pre-defined abilities or outcomes of training, graduating genetic counselors will be well prepared to enter the field with a minimum level of skills and abilities. A description of the Task Force's work, key changes and the 2013 PBCs are presented herein.
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http://dx.doi.org/10.1007/s10897-016-9984-3DOI Listing
October 2016

Triallelic and epigenetic-like inheritance in human disorders of telomerase.

Blood 2015 Jul 29;126(2):176-84. Epub 2015 May 29.

Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Barts Health, London, United Kingdom.

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres become critically short. This explains the major impact of the disease on highly proliferative tissues such as the bone marrow and skin. However, telomerase variants are not always fully penetrant and in some families disease-causing variants are seen in asymptomatic family members. As a result, determining the pathogenic status of newly identified variants in TERC or TERT can be quite challenging. Over a 3-year period, we have identified 26 telomerase variants (16 of which are novel) in 23 families. Additional investigations (including family segregation and functional studies) enabled these to be categorized into 3 groups: (1) disease-causing (n = 15), (2) uncertain status (n = 6), and (3) bystanders (n = 5). Remarkably, this process has also enabled us to identify families with novel mechanisms of inheriting human telomeropathies. These include triallelic mutations, involving 2 different telomerase genes, and an epigenetic-like inheritance of short telomeres in the absence of a telomerase mutation. This study therefore highlights that telomerase variants have highly variable functional and clinical manifestations and require thorough investigation to assess their pathogenic contribution.
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http://dx.doi.org/10.1182/blood-2015-03-633388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574016PMC
July 2015

Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations.

Am J Med Genet A 2015 Jul 21;167(7):1429-35. Epub 2015 Mar 21.

Van Andel Research Institute, Grand Rapids, Michigan.

Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS-targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria.
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http://dx.doi.org/10.1002/ajmg.a.37048DOI Listing
July 2015

Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature.

Am J Med Genet A 2014 Nov 12;164A(11):2879-86. Epub 2014 Aug 12.

Division of Genetic Medicine, Department of Pediatrics, University of Washington and Center for Integrative Brain Research Seattle Children's Research Institute, Seattle, Washington; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.

The microcephaly-lymphedema-chorioretinal dysplasia (MLCRD) syndrome is a distinct microcephaly syndrome. The hallmark features, microcephaly, chorioretinopathy, and lymphedema are frequently recognized at birth. Another clinical entity, the chorioretinal dysplasia, microcephaly and mental retardation syndrome (CDMMR) is a highly overlapping syndrome characterized by more variable lymphedema. Recently, heterozygous mutations in KIF11, a gene encoding a critical spindle motor protein of the Kinesin family, have been reported in individuals with MLCRD, and in individuals with CDMMR. This finding is suggestive of a single clinically variable spectrum. Here, we report on de novo novel mutations of KIF11 in five individuals with severe microcephaly, marked simplification of the gyral pattern on neuroimaging, bilateral chorioretinopathy, and developmental delay. Three patients had congenital lymphedema, and one had congenital bilateral sensorineural hearing loss. This report, therefore, further expands the clinical and molecular spectrum of KIF11-associated microcephaly.
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http://dx.doi.org/10.1002/ajmg.a.36707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205200PMC
November 2014

The genetics of luck.

Authors:
Helga V Toriello

Genet Med 2015 Feb 17;17(2):164-5. Epub 2014 Jul 17.

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.

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http://dx.doi.org/10.1038/gim.2014.87DOI Listing
February 2015

What is new in the field of genetics.

Authors:
Helga V Toriello

Adolesc Med State Art Rev 2013 Apr;24(1):43-56

Spectrum Health Hospitals, 25 Michigan St., Suite 2000, Grand Rapids, MI 49503, USA.

There is exciting research occurring the field of genetics and this article provides a summary of a few of the areas under active study, including chromosomal microarray, net-generation sequencing, and concepts of epigenetics. It is clear we do not have all the answers yet, but it is exciting to see what the future holds for our ability to diagnose and understand the causes of genetic disease. However, this is still not likely to be the end of the story, in that as we continue to study the human genome, we will continue to discover genetic influences on human health and disease.
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April 2013

Maternal vitamin K deficient embryopathy: association with hyperemesis gravidarum and Crohn disease.

Am J Med Genet A 2013 Mar 12;161A(3):417-29. Epub 2013 Feb 12.

Genetic Services, Spectrum Health, Grand Rapids, Michigan, USA.

Chondrodysplasia punctata (CDP) is an etiologically heterogeneous disorder characterized by the radiographic finding of stippled epiphyses (punctate calcifications). It is often accompanied by a characteristic facial appearance, known as the Binder phenotype, which is attributed to hypoplasia of the nasal cartilages; abnormal distal phalanges (brachytelephalangy) are a common component manifestation as well. We report eight patients with a Binder phenotype with or without CDP who all shared a known or suspected maternal deficiency of vitamin K. We suspect that this phenotype is probably under recognized, and we hope to increase awareness about the maternal risk factors, especially hyperemesis gravidarum, which lead to nutritional deficiency.
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http://dx.doi.org/10.1002/ajmg.a.35765DOI Listing
March 2013

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes.

Hum Mol Genet 2013 Apr 17;22(8):1654-62. Epub 2013 Jan 17.

Clinical Genetics, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.
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http://dx.doi.org/10.1093/hmg/ddt015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605834PMC
April 2013

American College of Medical Genetics and Genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing.

Genet Med 2013 Feb 17;15(2):150-2. Epub 2013 Jan 17.

Duke University Health System, Durham, NC, USA.

Genomic testing, including single-nucleotide polymorphism-based microarrays and whole-genome sequencing, can detect long stretches of the genome that display homozygosity. The presence of these segments, when distributed across multiple chromosomes, can indicate a familial relationship between the proband's parents. This article describes the detection of possible consanguinity by genomic testing and the factors confounding the inference of a specific p-arental relationship. It is designed to guide the documentation of suspected consanguinity by clinical laboratory professionals and to alert laboratories to the need to establish a reporting policy in conjunction with their ethics review committee and legal counsel.
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http://dx.doi.org/10.1038/gim.2012.169DOI Listing
February 2013

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing.

Genet Med 2013 Feb 3;15(2):153-6. Epub 2013 Jan 3.

Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.

MTHFR polymorphism testing is frequently ordered by physicians as part of the clinical evaluation for thrombophilia. It was previously hypothesized that reduced enzyme activity of MTHFR led to mild hyperhomocysteinemia which led to an increased risk for venous thromboembolism, coronary heart disease, and recurrent pregnancy loss. Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous t-hromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility and, therefore should not be ordered as a part of a routine evaluation for thrombophilia.
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http://dx.doi.org/10.1038/gim.2012.165DOI Listing
February 2013

Pancreatic insufficiency in Toriello-Carey syndrome: report of a second patient.

Am J Med Genet A 2012 May 11;158A(5):1208-11. Epub 2012 Apr 11.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Toriello-Carey syndrome is characterized by multiple congenital anomalies. Pancreatic insufficiency is suspected when patients present with poor weight gain, diarrhea, or maldigestion. The diagnosis is confirmed by low stool elastase and pancreatic stimulation testing. To our knowledge, only one patient with Toriello-Carey syndrome has been reported to have pancreatic insufficiency. We report on a second patient with Toriello-Carey syndrome and pancreatic insufficiency, and describe the management of pancreatic insufficiency in patients with this syndrome.
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http://dx.doi.org/10.1002/ajmg.a.35304DOI Listing
May 2012

Approach to the genetic evaluation of the child with autism.

Authors:
Helga V Toriello

Pediatr Clin North Am 2012 Feb;59(1):113-28, xi

Department of Pediatrics and Human Development (MSU), Michigan State University, College of Human Medicine, Secchia Center, 15 Michigan Street, Room 363, Grand Rapids, MI 49503, USA.

Autism is a heterogeneous entity that clearly has a substantial genetic component to its cause. There is likely enough evidence to suggest that there are common genetic mechanisms that predispose to various psychiatric disorders. More recent studies have attempted to identify the specific genes involved in predisposition to autism. In general, such conditions can be subdivided into metabolic, mitochondrial, chromosomal, and monogenic (ie, caused by mutation in a single gene). This article examines what conditions should be considered in the child who does not appear to have a syndromic cause as the reason for the autistic phenotype.
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http://dx.doi.org/10.1016/j.pcl.2011.10.014DOI Listing
February 2012

Thrombocytopenia-absent radius syndrome.

Authors:
Helga V Toriello

Semin Thromb Hemost 2011 Sep 18;37(6):707-12. Epub 2011 Nov 18.

Department of Clinical Genetics, Spectrum Health Hospitals, Grand Rapids, Michigan, USA.

Thrombocytopenia-absent radius (TAR) syndrome is a relatively uncommon condition characterized by absent radii with the presence of thumbs and congenital or early-onset thrombocytopenia that tends to resolve in childhood. The precise cause of this condition is unknown, although recently a microdeletion of chromosome 1q21.1 has been found in all investigated individuals. However, this microdeletion alone is not sufficient to cause TAR syndrome, and another, uncharacterized genetic alteration is thought to be involved in the pathogenesis.
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http://dx.doi.org/10.1055/s-0031-1291381DOI Listing
September 2011

Mosaic pentasomy X/tetrasomy X syndrome and premature ovarian failure.

Indian Pediatr 2011 May;48(5):402-4

Helen DeVos Childrens Hospital, Pediatric Endocrinology and Diabetes, Grand Rapids, MI 49503, USA.

A 16 year-old girl with pentasomy X mosaicism (47,XXX(1) 48,XXXX(12)/49,XXXXX) presented with primary amenorrhea. She had epicanthal folds, long philtrum, high-arched palate, facial asymmetry, short webbed neck, low posterior hairline, mild scoliosis, cubitus valgus, mental retardation and clinodactily. She was diagnosed with osteoporosis and premature ovarian failure.
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May 2011

Policy statement on folic acid and neural tube defects.

Genet Med 2011 Jun;13(6):593-6

Spectrum Health Hospitals and College of Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA.

It now recognized that the use of folate fortification and/or supplementation before initiation of pregnancy can impact the risk of the fetus developing a neural tube defect. This document serves to update the policy statement issued by the American College of Medical Genetics and published in 2005.
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http://dx.doi.org/10.1097/GIM.0b013e31821d4188DOI Listing
June 2011

Pigmentary anomalies and hearing loss.

Authors:
Helga V Toriello

Adv Otorhinolaryngol 2011 24;70:50-55. Epub 2011 Feb 24.

Genetics Services, Spectrum Health Hospitals, and College of Human Medicine, Michigan State University, Grand Rapids, Mich., USA.

A number of syndromes that include hearing loss in the phenotype also have pigmentary anomalies as a component manifestation. One of the most common of these is Waardenburg syndrome, which includes hypopigmentation and sensorineural hearing loss in the phenotype. There are four types of Waardenburg syndrome, distinguishable from each other by clinical findings. However, there are several other syndromes which include not only hypopigmentation, but also hyperpigmentation in the phenotype. This paper serves as a review of many of these syndromes.
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http://dx.doi.org/10.1159/000322471DOI Listing
May 2011

Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.

Am J Hum Genet 2010 Aug;87(2):219-28

Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.

Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2010.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917703PMC
August 2010

Gene doping: the hype and the harm.

Pediatr Clin North Am 2010 Jun;57(3):719-27

Spectrum Health Genetic Services, Grand Rapids, MI 49503, USA.

"Gene doping" is the term used to describe the potential abuse of gene therapy as a performance-enhancing agent. Gene doping would apply the techniques used in gene therapy to provide altered expression of genes that would promote physical superiority. For example, insulin-like growth factor 1 (IGF-1) is a primary target for growth hormone; overexpression of IGF-1 can lead to increased muscle mass and power. Although gene doping is still largely theoretical, its implications for sports, health, ethics, and medical genetics are significant.
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http://dx.doi.org/10.1016/j.pcl.2010.02.006DOI Listing
June 2010

Cilia and the ciliopathies: an introduction.

Am J Med Genet C Semin Med Genet 2009 Nov;151C(4):261-2

Michigan State University's College of Human Medicine, MI, USA.

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http://dx.doi.org/10.1002/ajmg.c.30230DOI Listing
November 2009

Evidence-based medicine and practice guidelines: application to genetics.

Am J Med Genet C Semin Med Genet 2009 Aug;151C(3):235-40

Spectrum Health-Genetics, 25 Michigan St. Suite 2000, Grand Rapids, MI 49503, USA.

The Professional Practice and Guidelines Committee of the American College of Medical Genetics has the responsibility of overseeing the development of guidelines for the practice of clinical genetics. In the past, most, if not all, guidelines were primarily based on expert opinion. However, recently the goal has become to develop guidelines that are more evidence-based, or at least, to recognize the level of evidence available to the authors of these documents. This article reviews the challenges that are faced by geneticists who are charged with the development of practice guidelines.
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http://dx.doi.org/10.1002/ajmg.c.30222DOI Listing
August 2009