Publications by authors named "Shane C Quinonez"

25 Publications

  • Page 1 of 1

The introduction of genetic counseling in Ethiopia: Results of a training workshop and lessons learned.

PLoS One 2021 23;16(7):e0255278. Epub 2021 Jul 23.

Department of Pediatrics, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.

Background: Over the past two decades non-communicable diseases (NCDs) have steadily increased as a cause of worldwide disability and mortality with a concomitant decrease in disease burden from communicable, maternal, neonatal and nutritional conditions. Congenital anomalies, the most common NCD affecting children, have recently become the fifth leading cause of under-five mortality worldwide, ahead of other conditions such as malaria, neonatal sepsis and malnutrition. Genetic counseling has been shown to be an effective method to decrease the impact of congenital anomalies and genetic conditions but is absent in almost all sub-Saharan Africa countries. To address this need for counseling services we designed and implemented the first broad-based genetic counseling curriculum in Ethiopia, launching it at St. Paul's Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia.

Methods: The curriculum, created by Michigan Medicine and SPHMMC specialists, consisted of medical knowledge and genetic counseling content and was delivered to two cohorts of nurses. Curriculum evaluation consisted of satisfaction surveys and pre- and post-assessments covering medical knowledge and genetic counseling content. Following Cohort 1 training, the curriculum was modified to increase the medical knowledge material and decrease Western genetic counseling principles material.

Results: Both cohorts reported high levels of satisfaction but felt the workshop was too short. No significant improvements in assessment scores were seen for Cohort 1 in terms of total scores and medical knowledge and genetic counseling-specific questions. Following curriculum modification, improvements were seen in Cohort 2 with an increase in total assessment scores from 63% to 73% (p = 0.043), with medical knowledge-specific questions increasing from 57% to 79% (p = 0.01) with no significant change in genetic counseling-specific scores. Multiple logistic, financial, cultural and systems-specific barriers were identified with recommendations for their consideration presented.

Conclusion: Genetics medical knowledge of Ethiopian nurses increased significantly following curriculum delivery though difficulty was encountered with Western genetic counseling material.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255278PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301664PMC
July 2021

The introduction of clinical genetic testing in Ethiopia: Experiences and lessons learned.

Am J Med Genet A 2021 10 24;185(10):2995-3004. Epub 2021 Jun 24.

MRC-ET Advanced Laboratory, Addis Ababa, Ethiopia.

Limited data are available on genetic testing laboratories in low- and middle-income countries including those in sub-Saharan Africa (SSA). To characterize the need for genetic testing in SSA we describe the experience of MRC-ET Advanced Laboratory, a genetic testing laboratory in Ethiopia. Test results were analyzed based on indication(s) for testing, referral category, and diagnostic yield. A total of 1311 tests were run using the full MRC-Holland catalogue of Multiplex-Ligation Probe Amplification assays. Of all samples, 77% were postnatal samples, 15% products of conception (POC), and 8% amniotic samples. Of postnatal samples, the most common testing categories were multiple congenital anomalies (32%), disorders of sex development (17%), and Obstetrics/Gynecology (16%). Forty-three percent of postnatal samples were diagnostic, 11% were variants of uncertain significance (VUS), and 46% were normal with Trisomy 21 the most common diagnosis. Of POC samples, 10% were diagnostic, 34% revealed VUSs, and 55% were normal with Trisomy 18 the most common diagnosis. Of amniotic samples 17.5% were diagnostic, 3% revealed VUSs, and 79% were normal with Trisomy 18 the most common diagnosis. There is increasing demand for genetic testing in Ethiopia. Diagnostic genetic testing in SSA deserves increased attention as testing platforms become more affordable.
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http://dx.doi.org/10.1002/ajmg.a.62396DOI Listing
October 2021

Trainee perspectives of COVID-19 impact on medical genetics education.

Genet Med 2021 05 12;23(5):956-962. Epub 2021 Feb 12.

Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA.

Purpose: The SARS-CoV-2 pandemic abruptly altered medical education and clinical care. This work evaluates trainee perspectives of the impact of the pandemic on medical genetics education.

Methods: A Qualtrics survey was sent to physician trainees who rotated in genetics before or midpandemic. Questions assessed patient care, didactic education, and competency in multiple domains. Number of clinic visits completed by trainees were collated through review of documentation.

Results: Twenty-three rotating residents completed the surveys. Five of the pediatric residents completed the elective during the pandemic. All residents participated in virtual care during the pandemic, and rotating residents reported an improvement in self-assessed competency in multiple domains. Potential weak areas of education midpandemic included dysmorphology and genetic counseling.

Conclusion: Residents on a genetics elective can gain crucial skills and knowledge even when the rotation is in a primarily virtual format. Supplemental dysmorphology and genetic counseling education may improve remote educational experiences. Further research across institutions may deepen understanding of the impact of the pandemic on education in genetics.
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http://dx.doi.org/10.1038/s41436-020-01072-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880658PMC
May 2021

Knowledge and attitudes about genetic counseling in patients at a major hospital in Addis Ababa, Ethiopia.

J Genet Couns 2021 04 28;30(2):544-552. Epub 2020 Oct 28.

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

Previous work at St. Paul's Hospital Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia, demonstrated a need for genetic counseling (GC) services, with 4% of pediatric, neonatal intensive care, and prenatal patients identified as having indications for genetic evaluation (Quinonez et al, 2019). The aim of this study was to investigate SPHMMC patients' familiarity with, knowledge of, and attitudes toward GC services. Surveys were adapted from previous work in North America populations (Riesgraf et al, 2015 and Gemmell et al, 2017) and administered to 102 patients, and results were compared to North American populations using Student's t test. 30% of respondents reported at least some familiarity with GC, primarily via the media or healthcare providers. Patients had generally positive attitudes toward GC, reporting they would trust information provided by a genetic counselor and that GC is in line with their values. Knowledge of GC showed similar trends overall when compared to results from North American populations. Our work indicates limited exposure to GC in this population, but generally positive feelings toward GC. Patients' attitudes toward GC were comparable to rural North American populations surveyed using the same tool on most items; however, cultural differences including views on abortions and directiveness of healthcare providers could account for discrepancies and are important considerations when implementing genetic services globally.
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http://dx.doi.org/10.1002/jgc4.1340DOI Listing
April 2021

The diagnosis of inborn errors of metabolism in previously undiagnosed adults referred for medical genetics evaluation.

Mol Genet Metab Rep 2020 Dec 1;25:100653. Epub 2020 Oct 1.

Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, 24 Frank Lloyd Wright Dr., GPS: 4029 Ave Maria Drive Lobby C, Suite 1300 Ann Arbor, 48105 Ann Arbor, MI, USA.

Traditionally thought of as a pediatric diagnostic and therapeutic dilemma, the diagnostic rate and spectrum of inborn errors of metabolism (IEM) in the adult population is largely unknown. A retrospective chart review of patients seen by the Michigan Medicine Adult Medical Genetics Clinic for clinical evaluation from 2014 to 2018 was conducted. Patients referred for a primary indication possibly consistent with an IEM were considered. Variables included age at genetic evaluation, symptom onset age, sex, clinical course, organ systems involved, developmental history, family history and prior genetic testing. Of patients evaluated during the study period, 112 were referred for an indication possibly consistent with an IEM and underwent a complete biochemical workup with an IEM diagnostic rate of 9.8% achieved. An additional 9.8% were diagnosed with a non-IEM genetic diagnosis. Management changes were implemented in all IEM diagnoses. Metabolic disorders in the adult population are under-recognized and under-diagnosed. This report demonstrates the need for clinicians to consider these diagnoses in adults and either refer to a genetics clinic or initiate a biochemical workup. As advances in diagnosis, treatment, and life expectancy of patients with IEMs increases, recognizing and diagnosing these conditions can significantly impact care.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549142PMC
December 2020

Dramatic Improvement in Seizures With Phenytoin Treatment in an Individual With Refractory Epilepsy and a SCN1B Variant.

Pediatr Neurol 2020 07 19;108:121-122. Epub 2020 Mar 19.

Division of Pediatric Neurology, Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.012DOI Listing
July 2020

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

Pediatr Res 2020 03 16;87(4):735-739. Epub 2019 Oct 16.

Division of Pediatric Genetics, Metabolism, and Genomic Medicine, Department of Pediatrics, University of Michigan, Arbor, MI, USA.

Background: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate.

Methods: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES.

Results: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice.

Conclusions: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.
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http://dx.doi.org/10.1038/s41390-019-0611-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082194PMC
March 2020

Infantile onset Pompe disease presenting with non-immune hydrops fetalis.

Mol Genet Metab Rep 2019 Dec 21;21:100503. Epub 2019 Aug 21.

Department of Pediatrics, Division of Pediatric Genetics, Metabolism and Genomic Medicine, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1016/j.ymgmr.2019.100503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713818PMC
December 2019

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

Genet Med 2020 02 7;22(2):389-397. Epub 2019 Aug 7.

Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function.

Methods: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains.

Results: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains.

Conclusion: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
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http://dx.doi.org/10.1038/s41436-019-0612-0DOI Listing
February 2020

Patient preferences for prenatal testing and termination of pregnancy for congenital anomalies and genetic diseases in Ethiopia.

Prenat Diagn 2019 07 18;39(8):595-602. Epub 2019 Jun 18.

Department of Pediatrics, Division of Genetics, Metabolism, and Genomic Medicine, University of Michigan, Ann Arbor, MI, USA.

Objective: As prenatal diagnostic services expand throughout low-income countries, an important consideration is the appropriateness of these services for patients. In these countries, services now include prenatal ultrasound and occasionally genetic testing. To assess patient interest, we surveyed pregnant patients at a hospital in Addis Ababa, Ethiopia, on their preferences for prenatal testing and termination of affected pregnancies for congenital anomalies and genetic diseases.

Method: One hundred one pregnant patients were surveyed on their preferences for prenatal testing and termination of affected pregnancies using a survey covering various congenital anomalies and genetic diseases.

Results: Eighty-nine percent of patients reported interest in testing for all conditions. Three percent of patients were not interested in any testing. Over 60% of patients reported interest in termination for anencephaly, early infant death, severe intellectual disability, hemoglobinopathy, and amelia. Patients were more likely to express interest in prenatal testing and termination for conditions associated with a shortened lifespan.

Conclusion: Ethiopian patients were interested in prenatal testing and termination of pregnancy for many conditions. Advancing prenatal diagnostic capacities is a potential strategy for addressing the incidence of congenital anomalies and genetic disease in Ethiopia. Importantly, there exist many factors and technological limitations to consider before implementation.
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http://dx.doi.org/10.1002/pd.5472DOI Listing
July 2019

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Hum Mutat 2019 07 24;40(7):908-925. Epub 2019 Apr 24.

Department of Metabolic Medicine, The Royal Children's Hospital, Melbourne, Parkville, Victoria, Australia.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.
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http://dx.doi.org/10.1002/humu.23731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661012PMC
July 2019

DNA LIGASE IV SYNDROME: A RARE CAUSE OF GROWTH FAILURE & HYPOGONADISM.

AACE Clin Case Rep 2019 Mar-Apr;5(2):e154-e158. Epub 2018 Nov 1.

Objective: DNA ligase IV syndrome is a rare genetic disorder characterized by pronounced radiosensitivity, growth failure, pancytopenia, hypogonadism, and immunodeficiency. Here, we describe a unique case of DNA ligase IV syndrome diagnosed in adulthood and review the endocrine manifestations of this rare disorder.

Methods: We present detailed clinical, laboratory, and exam findings and review the relevant literature.

Results: This patient initially presented in childhood with microcephaly, growth failure, and mild pancytopenia. At age 18, she developed secondary amenorrhea, with labs revealing hypergonadotropic hypogonadism. She was initially suspected to have Turner syndrome, but karyotype testing was normal. At age 34, genetic testing ultimately confirmed the diagnosis of DNA ligase IV syndrome.

Conclusion: Severe growth failure and hypogonadism are important endocrine clues to the diagnosis of DNA ligase IV syndrome. The increased availability of genetic testing and whole-exome sequencing may allow for definitive diagnosis in patients that previously went unrecognized.
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http://dx.doi.org/10.4158/ACCR-2018-0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873855PMC
November 2018

Introducing medical genetics services in Ethiopia using the MiGene Family History App.

Genet Med 2019 02 11;21(2):451-458. Epub 2018 Jun 11.

Department of Pediatrics and Child Health, St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.

Purpose: Almost all low-income countries and many middle-income countries lack the capacity to deliver medical genetics services. We developed the MiGene Family History App (MFHA), which assists doctors with family history collection and population-level epidemiologic analysis. The MFHA was studied at St. Paul's Hospital in Addis Ababa, Ethiopia.

Methods: A needs assessment was used to assess Ethiopian physicians' experience with genetics services. The MFHA then collected patient data over a 6-month period.

Results: The majority of doctors provide genetics services, with only 16% reporting their genetics knowledge is sufficient. A total of 1699 patients from the pediatric ward (n = 367), neonatal intensive care unit (NICU) (n = 477), and antenatal clinic (n = 855) were collected using the MFHA with a 4% incidence of a MFHA-screened condition present. The incidence was 11.7% in the pediatric ward, 3% in the NICU, and 0.5% in the antenatal clinic. Heart malformations (5.5% of patients) and trisomy 21 (4.4% of patients) were the most common conditions in the pediatric ward.

Conclusion: Medical genetics services are needed in Ethiopia. As other countries increase their genetics capacity, the MFHA can provide fundamental genetics services and collect necessary epidemiologic data.
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http://dx.doi.org/10.1038/s41436-018-0069-6DOI Listing
February 2019

The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later.

J Genet Couns 2017 Oct 13;26(5):894-901. Epub 2017 Jun 13.

Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan, 300 North Ingalls, NI3 A03, SPC 5419, Ann Arbor, MI, 48109, USA.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re-evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family's clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that "the patient" can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient's daughter's pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient's husband's internet search of his wife's clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re-evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.
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http://dx.doi.org/10.1007/s10897-017-0119-2DOI Listing
October 2017

A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

Am J Med Genet A 2017 Jan 14;173(1):268-273. Epub 2016 Oct 14.

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

Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38000DOI Listing
January 2017

Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency.

JIMD Rep 2017 13;34:55-61. Epub 2016 Aug 13.

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.

Holocarboxylase synthetase (HLCS) deficiency is a rare autosomal recessive disorder that presents with multiple life-threatening metabolic derangements including metabolic acidosis, ketosis, and hyperammonemia. A majority of HLCS deficiency patients respond to biotin therapy; however, some patients show only a partial or no response to biotin therapy. Here, we report a neonatal presentation of HLCS deficiency with partial response to biotin therapy. Sequencing of HLCS showed a novel heterozygous mutation in exon 5, c.996G>C (p.Gln332His), which likely abolishes the normal intron 6 splice donor site. Cytogenetic analysis revealed that the defect of the other allele is a paracentric inversion on chromosome 21 that disrupts HLCS. This case illustrates that in addition to facilitating necessary family testing, a molecular diagnosis can optimize management by providing a better explanation of the enzyme's underlying defect. It also emphasizes the potential benefit of a karyotype in cases in which molecular genetic testing fails to provide an explanation.
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http://dx.doi.org/10.1007/8904_2016_9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509548PMC
August 2016

Newborn screening for dihydrolipoamide dehydrogenase deficiency: Citrulline as a useful analyte.

Mol Genet Metab Rep 2014 15;1:345-349. Epub 2014 Aug 15.

University of Michigan, Department of Pediatrics, Division of Pediatric Genetics, 1500 East Medical Center Drive, D5240 MPB/Box 5718, Ann Arbor, MI 48109-5718, USA.

Dihydrolipoamide dehydrogenase deficiency, also known as maple syrup urine disease (MSUD) type III, is caused by the deficiency of the E3 subunit of branched chain alpha-ketoacid dehydrogenase (BCKDH), α-ketoglutarate dehydrogenase (αKGDH), and pyruvate dehydrogenase (PDH). DLD deficiency variably presents with either a severe neonatal encephalopathic phenotype or a primarily hepatic phenotype. As a variant form of MSUD, it is considered a core condition recommended for newborn screening. The detection of variant MSUD forms has proven difficult in the past with no asymptomatic DLD deficiency patients identified by current newborn screening strategies. Citrulline has recently been identified as an elevated dried blood spot (DBS) metabolite in symptomatic patients affected with DLD deficiency. Here we report the retrospective DBS analysis and second-tier allo-isoleucine testing of 2 DLD deficiency patients. We show that an elevated citrulline and an elevated allo-isoleucine on second-tier testing can be used to successfully detect DLD deficiency. We additionally recommend that DLD deficiency be included in the "citrullinemia/elevated citrulline" ACMG Act Sheet and Algorithm.
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http://dx.doi.org/10.1016/j.ymgmr.2014.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121342PMC
August 2014

Human HOX gene disorders.

Mol Genet Metab 2014 Jan 29;111(1):4-15. Epub 2013 Oct 29.

University of Michigan, Department of Pediatrics, Division of Pediatric Genetics, 1500 East Medical Center Drive, D5240 MPB/Box 5718, Ann Arbor, MI 48109-5718, USA; University of Michigan, Department of Human Genetics, 1241 E. Catherine, 4909 Buhl Building, Ann Arbor, MI 48109-5618, USA. Electronic address:

The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.
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http://dx.doi.org/10.1016/j.ymgme.2013.10.012DOI Listing
January 2014

9p partial monosomy and disorders of sex development: review and postulation of a pathogenetic mechanism.

Am J Med Genet A 2013 Aug 3;161A(8):1882-96. Epub 2013 Jul 3.

Department of Pediatrics, Division of Genetics, University of Michigan, Ann Arbor, MI, USA.

Deletion of the distal segment of 9p causes a syndrome comprising trigonocephaly, minor anomalies, and intellectual disability. Patients with this condition also frequently present with genitourinary abnormalities including cryptorchidism, hypospadias, ambiguous genitalia, or 46,XY testicular dysgenesis. The region responsible for the gonadal dysgenesis has been localized to 9p24.3 with the likely responsible gene identified as DMRT1. Similar to patients with other molecular causes of 46,XY gonadal dysgenesis, patients with partial del 9p have an increased risk of gonadoblastoma. We present two patients with 46,XY gonadal dysgenesis due to partial 9p monosomy. Both patients were also diagnosed with gonadoblastoma following gonadectomy at an early age. Chromosomal microarray analyses refined the cytogenetic abnormalities and allowed potential genotype-phenotype relationships to be determined. We also review the literature as it pertains to partial 9p monosomy, genital abnormalities and gonadoblastoma and note that a large percentage of affected patients present with two copy number variations. We propose that a two-hit mechanism may be involved in the incomplete penetrance and variable expressivity of partial 9p monosomy and an abnormal genital phenotype. The significant percentage of gonadoblastoma in patients with 46,XY complete gonadal dysgenesis due to partial 9p monosomy also continues to support the necessity of gonadectomy in this patient population.
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http://dx.doi.org/10.1002/ajmg.a.36018DOI Listing
August 2013

Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation.

Am J Med Genet A 2013 May 26;161A(5):1019-27. Epub 2013 Mar 26.

Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109-5618, USA.

Polyalanine repeat expansion diseases are hypothesized to result from unequal chromosomal recombination, yet mechanistic studies are lacking. We identified two de novo cases of hand-foot-genital syndrome (HFGS) associated with polyalanine expansions in HOXA13 that afforded rare opportunities to investigate the mechanism. The first patient with HFGS was heterozygous for a de novo nine codon polyalanine expansion. Haplotype investigation showed that the expansion arose on the maternally inherited chromosome but not through unequal crossing over between homologs, leaving unequal sister chromatid exchange during mitosis or meiosis or slipped mispairing as possible explanations. The asymptomatic father of the second patient with HFGS was mosaic for a six codon polyalanine expansion. Multiple tissue PCR and clonal analysis of paternal fibroblasts showed only expansion/WT and WT/WT clones, and haplotype data showed that two unaffected offspring inherited the same paternal allele without the expansion, supporting a postzygotic origin. Absence of the contracted allele in the mosaic father does not support sister chromatid exchange in the origin of the expansion. Mosaicism for HOXA13 polyalanine expansions may be associated with a normal phenotype, making examination of parental DNA essential in apparently de novo HFGS cases to predict accurate recurrence risks. We could not find an example in the literature where unequal sister chromatid exchange has been proven for any polyalanine expansion, suggesting that the principal mechanism for polyalanine expansions (and contractions) is slipped mispairing without repair or that the true frequency of unequal sister chromatid exchange involving these repeats is low.
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http://dx.doi.org/10.1002/ajmg.a.35843DOI Listing
May 2013

Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency.

Pediatr Neurol 2013 Jan;48(1):67-72

Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.

We present the biochemical and molecular diagnosis of dihydrolipoamide dehydrogenase deficiency (also known as E3 deficiency) and Leigh syndrome in a 14-year-old girl with learning disability and episodic encephalopathy and ketoacidosis. The diagnosis was based on values of plasma amino acids and urine organic acids, obtained during acute encephalopathy, lactic ketoacidosis, and liver failure, precipitated by infectious mononucleosis. Enzymatic and molecular analyses confirmed dihydrolipoamide dehydrogenase deficiency. E3 activity from cultured skin fibroblasts ranged from 9-29% of the mean. Molecular analysis revealed compound heterozygosity for novel and known pathogenic mutations (p.I353T and p.G136del, respectively). The patient received dietary augmentation and continuous renal replacement therapy, given her severe, persistent lactic acidosis. Acute decompensation resulted in magnetic resonance imaging changes involving the posterior aspect of the putamen, lateral, and medial thalami, substantia nigra, lateral geniculate bodies, and splenium of the corpus callosum. The cortex and subcortical white matter of the right and left occipital lobes and perirolandic region were also affected. In our review of molecularly confirmed patients with dihydrolipoamide dehydrogenase deficiency, Leigh syndrome was common. Our patient, whose most severe decompensation occurred at a more advanced age than previously reported, provides further evidence of the heterogeneous presentations of dihydrolipoamide dehydrogenase deficiency.
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http://dx.doi.org/10.1016/j.pediatrneurol.2012.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535688PMC
January 2013

Maternal intrachromosomal insertional translocation leads to recurrent 1q21.3q23.3 deletion in two siblings.

Am J Med Genet A 2012 Oct 17;158A(10):2591-601. Epub 2012 Aug 17.

Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, USA.

We identified a novel 6.33 Mb deletion of 1q21.3q23.3 (hg18; chr1: 153035245-159367106) in two siblings presenting with blepharophimosis, ptosis, microbrachycephaly, severe psychomotor, and intellectual disability. Additional common features include small corpus callosum, normal birth length and head circumference, postnatal growth restriction, low anterior hairline, upturned nose, bilateral preauricular pits, widely spaced teeth, gingival hypertrophy, left ventricular dilatation with decreased biventricular systolic function, delayed bone age, 5th finger clinodactyly, short 3rd digit, hyperconvex nails, obstructive and central sleep apnea, and bilateral heel contractures. Fluorescence in situ hybridization (FISH) performed in the mother of both children showed an apparently balanced, intrachromosomal insertional translocation of 1q21.3q23.3 to 1q42.12. The sibling recurrence likely arose by a maternal meiotic crossing over on the rearranged chromosome 1 between the deleted region and the insertion. We hypothesize that the decreased cardiac function and contractures may be related to LMNA haploinsufficiency. This case illustrates the importance of FISH when attempting to determine inheritance of a copy-number variation and emphasize the value of evaluating known haploinsufficiency phenotypes for genes in deleted regions.
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http://dx.doi.org/10.1002/ajmg.a.35563DOI Listing
October 2012
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