Publications by authors named "Donald Basel"

49 Publications

Molecular mechanics and dynamic simulations of well-known Kabuki syndrome-associated KDM6A variants reveal putative mechanisms of dysfunction.

Orphanet J Rare Dis 2021 Feb 5;16(1):66. Epub 2021 Feb 5.

Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Kabuki syndrome is a genetic disorder that affects several body systems and presents with variations in symptoms and severity. The syndrome is named for a common phenotype of faces resembling stage makeup used in a Japanese traditional theatrical art named kabuki. The most frequent cause of this syndrome is mutations in the H3K4 family of histone methyltransferases while a smaller percentage results from genetic alterations affecting the histone demethylase, KDM6A. Because of the rare presentation of the latter form of the disease, little is known about how missense changes in the KDM6A protein sequence impact protein function.

Results: In this study, we use molecular mechanic and molecular dynamic simulations to enhance the annotation and mechanistic interpretation of the potential impact of eleven KDM6A missense variants found in Kabuki syndrome patients. These variants (N910S, D980V, S1025G, C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W, and R1351Q) are predicted to be pathogenic, likely pathogenic or of uncertain significance by sequence-based analysis. Here, we demonstrate, for the first time, that although Kabuki syndrome missense variants are found outside the functionally critical regions, they could affect overall function by significantly disrupting global and local conformation (C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W and R1351Q), chemical environment (C1153R, C1153Y, P1195L, L1200F, Q1212R, Q1248R, R1255W and R1351Q), and/or molecular dynamics of the catalytic domain (all variants). In addition, our approaches predict that many mutations, in particular C1153R, could allosterically disrupt the key enzymatic interactions of KDM6A.

Conclusions: Our study demonstrates that the KDM6A Kabuki syndrome variants may impair histone demethylase function through various mechanisms that include altered protein integrity, local environment, molecular interactions and protein dynamics. Molecular dynamics simulations of the wild type and the variants are critical to gain a better understanding of molecular dysfunction. This type of comprehensive structure- and MD-based analyses should help develop improved impact scoring systems to interpret the damaging effects of variants in this protein and other related proteins as well as provide detailed mechanistic insight that is not currently predictable from sequence alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01692-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866879PMC
February 2021

A Deep Intronic Variant Activates a Pseudoexon in the Gene in a Family with X-Linked Myotubular Myopathy.

Mol Syndromol 2020 Dec 16;11(5-6):264-270. Epub 2020 Sep 16.

Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.

We report a novel intronic variant in the gene in 4 males in a family with severe X-linked myotubular myopathy. The A>G variant in deep intronic space activates a cryptic 5' donor splice site resulting in the inclusion of a 48-bp pseudoexon into the mature mRNA. The variant is present in all affected males, absent in unaffected males, and heterozygous in the mother of the affected males. The included intronic sequence contains a premature stop codon, and experiments using a translational inhibitor indicate that the mutant mRNAs undergo nonsense-mediated decay. We conclude that affected males produce no, or low, levels of mRNA likely leading to a significant reduction of myotubularin-1 protein resulting in the severe neonatal myopathy present in this family. The study highlights the need to consider noncoding variants in genomic screening in families with X-linked myotubular myopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000510286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802444PMC
December 2020

Photodynamic Therapy for Benign Cutaneous Neurofibromas Using Aminolevulinic Acid Topical Application and 633 nm Red Light Illumination.

Photobiomodul Photomed Laser Surg 2021 Jan 20. Epub 2021 Jan 20.

Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Neurofibromatosis type 1 (NF1) has no current effective treatments beyond surgery. Topical photodynamic therapy (PDT) has the potential to provide a less invasive treatment modality. Based on murine data, we hypothesized PDT could be used for the treatment of cutaneous neurofibromas (cNF). We conducted a phase I trial to examine absorption and conversion of topical aminolevulinic acid (ALA) in cNF and determine safety in a dose escalation study. ALA or control vehicle was applied to neurofibromas through microneedle-assisted delivery ( = 4) and excised specimens were examined 24 h later for protoporphyrin IX fluorescence. Fluorescence was detected in the tumors at 304 ± 94 U/μm, while adjacent paralesional normal skin and vehicle-treated tumors showed no fluorescence ( < 0.0001). Subsequently, neurofibromas ( = 27) were treated with ALA and irradiated with 633 nm red light 18 h later, at escalating dosages of 50 and 100 mJ/cm. Maximum tolerable dose was established at 100 mJ/cm. Light microscopy study of tumors biopsied 48 h after PDT (ALA  = 14 and vehicle  = 4) showed mixed inflammatory infiltrate in the ALA, but not in the vehicle-treated tumors or perilesional normal skin. TUNEL evaluation showed 42.5 ± 19.9 apoptotic cells per visual field for ALA-treated and 1.1 ± 1.4 for vehicle-treated tumors ( = 0.002). In the first reported clinical trial of PDT for NF1, PDT targeted neurofibromas specifically, and may offer a normal tissue-sparing treatment modality in the future. This study is registered at Clintrials.gov (NCT01682811).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/photob.2020.4957DOI Listing
January 2021

Missense variant contribution to USP9X-female syndrome.

NPJ Genom Med 2020 Dec 9;5(1):53. Epub 2020 Dec 9.

University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia.

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-020-00162-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725775PMC
December 2020

Adaptive Behavior and Executive Functioning in Children with Neurofibromatosis Type 1 Using a Mixed Design.

J Dev Behav Pediatr 2020 Oct-Nov;41(8):637-643

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI.

Objective: Children with neurofibromatosis type 1 (NF1) demonstrate poorer adaptive functioning compared with same-aged peers; however, there is limited research about the longitudinal pattern of adaptive behavior. The aim of this investigation was to examine parent-reported adaptive behavior of children with NF1 longitudinally beginning in early childhood and to examine relations with executive functioning.

Method: Children with NF1 were assessed during early childhood (n = 59; aged 3-7; mean = 4.8, SD = 1.42) or school age (n = 39; aged 9-13; mean = 10.85, SD = 1.58), and a subset was seen at both time points (n = 26). The Scales of Independent Behavior-Revised was used to assess adaptive functioning, and the Behavior Rating Inventory of Executive Function-Preschool Version/Behavior Rating Inventory of Executive Function was used to evaluate everyday executive functioning.

Results: Adaptive behavior in early childhood was significantly correlated with adaptive behavior at school age (with the exception of social interaction and communication skills) and was significantly poorer at school age. The frequency of difficulties increased over time for overall adaptive behavior and motor skills. Executive functioning was related to adaptive behavior cross-sectionally within early childhood and at school age and showed longitudinal predictive value over time.

Conclusion: This research contributes to the limited NF1 adaptive behavior literature by characterizing the longitudinal pattern of adaptive behavior and relations with executive abilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DBP.0000000000000833DOI Listing
October 2020

Café au lait spots: When and how to pursue their genetic origins.

Clin Dermatol 2020 Jul - Aug;38(4):421-431. Epub 2020 Mar 25.

Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Café au lait spots are common birthmarks seen sporadically and in association with several genetic syndromes. Dermatologists are often asked to evaluate these birthmarks both by other physicians and by parents. In some cases, it is challenging to know when and how to pursue further evaluation. Diagnostic challenges may come in the form of the appearance of the individual lesions, areas and patterns of cutaneous involvement, and associated features (or lack thereof). In this review, we aim to clarify when and how to evaluate the child with multiple or patterned café au lait spots and to explain some emerging concepts in our understanding of the genetics of these lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clindermatol.2020.03.005DOI Listing
October 2020

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

Lancet 2020 09;396(10252):684-692

BioMarin (UK), London, UK.

Background: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings.

Methods: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.

Findings: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.

Interpretation: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be.

Funding: BioMarin Pharmaceutical.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(20)31541-5DOI Listing
September 2020

Liver failure and x-linked immunodeficiency type 47.

Pediatr Transplant 2020 12 13;24(8):e13808. Epub 2020 Aug 13.

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

Patients with defects in the ATP6AP1 gene have rarely been described. ATP6AP1-related disorders are a subtype of CDG, which result in enzyme deficiencies affecting multiple organ systems ranging from mild to life-threatening. Of the 13 patients described, all had hepatopathy, but this is the first case to be successfully transplanted. We describe two brothers who developed hyperbilirubinemia shortly after birth and progressed to liver failure, case 1 by 12 months of age, with successful transplant 2 years later, and case 2 by 4 months of age, who passed away while awaiting liver transplant. Both boys were found to have a new variant in the ATP6AP1 gene: c.932/p.Leu311Gln. Although the identified ATP6AP1 gene variant was classified as unknown significance at the time, both children's phenotypes fit with what has been described for ATP6AP1-related disorders. Therefore, this result appears to have been diagnostic for both boys. This rare type of CDG, X-linked immunodeficiency type 47 (OMIM #300972), particularly in patients who progress to liver failure requiring transplant, should be included on the differential of liver failure in infants and toddlers, and its gene should be added to the diagnostic workup for such cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13808DOI Listing
December 2020

Compound heterozygous splicing CDON variants result in isolated ocular coloboma.

Clin Genet 2020 Nov 17;98(5):486-492. Epub 2020 Aug 17.

Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, Wisconsin, USA.

Ocular coloboma is caused by failure of optic fissure closure during development and recognized as part of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum. While many genes are known to cause colobomatous microphthalmia, relatively few have been reported in coloboma with normal eye size. Genetic analysis including trio exome sequencing and Sanger sequencing was undertaken in a family with two siblings affected with bilateral coloboma of the iris, retina, and choroid. Pathogenic variants in MAC genes were excluded. Trio analysis identified compound heterozygous donor splice site variants in CDON, a cell-surface receptor known to function in the Sonic Hedgehog pathway, c.928 + 1G > A and c.2650 + 1G > T, in both affected individuals. Heterozygous missense and truncating CDON variants are associated with dominant holoprosencephaly (HPE) with incomplete penetrance and Cdon-/- mice display variable HPE and coloboma. A homozygous nonsense allele of uncertain significance was recently identified in a consanguineous patient with coloboma and a second molecular diagnosis. We report the first compound heterozygous variants in CDON as a cause of isolated coloboma. CDON is the first HPE gene identified to cause recessive coloboma. Given the phenotypic overlap, further examination of HPE genes in coloboma is indicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13824DOI Listing
November 2020

Dysmorphology in a Genomic Era.

Authors:
Donald Basel

Clin Perinatol 2020 03 31;47(1):15-23. Epub 2019 Oct 31.

Department of Pediatrics, Division of Genetics, Medical College of Wisconsin, 9000 West Wisconsin Avenue, MS #716, Milwaukee, WI 53226, USA. Electronic address:

Dysmorphology is the practice of defining the morphologic phenotype of syndromic disorders. Genomic sequencing has advanced our understanding of human variation and molecular dysmorphology has evolved in response to the science of relating embryologic developmental implications of abnormal gene signaling pathways to the resultant phenotypic presentation. Machine learning has enabled the application of deep convoluted neural networks to recognize the comparative likeness of these phenotypes relative to the causal genotype or disrupted gene pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clp.2019.10.009DOI Listing
March 2020

Mitochondrial DNA Depletion Syndromes.

Authors:
Donald Basel

Clin Perinatol 2020 03 31;47(1):123-141. Epub 2019 Oct 31.

Department of Pediatrics, Division of Genetics, Medical College of Wisconsin, 9000 West Wisconsin Avenue, MS #716, Milwaukee, WI 53226, USA. Electronic address:

Mitochondrial disorders present in a myriad of ways, which causes them to be included in the differential diagnosis for many patients with undiagnosed disease. A subset of mitochondrial disorders are caused by intrinsic defects in the mitochondrial replication machinery, leading to loss of cellular mitochondrial content over time. The diagnosis of mitochondrial disease is complex. Several best-practice guides are available that enable a higher likelihood of detecting a mitochondrial disorder. The application of genomic sequencing and advanced physiologic analysis of the electron transport chain can offer more definitive evidence of mitochondrial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clp.2019.10.008DOI Listing
March 2020

Undiagnosed and Rare Diseases in Perinatal Medicine: Lessons in Context and Cognitive Diagnostic Error.

Clin Perinatol 2020 03 7;47(1):1-14. Epub 2019 Oct 7.

Department of Pediatrics, Section of Rheumatology, Nelson Service for Undiagnosed and Rare Diseases, Children's Hospital of Wisconsin, Medical College of Wisconsin, 999 North 92nd Street, Suite C465, Milwaukee, WI 53226, USA.

Critically ill neonates experience high rates of morbidity and mortality. Major diagnostic errors are identified in up to 20% of autopsied neonatal intensive care unit deaths. Neonates with undiagnosed or rare congenital disorders may mimic critically ill neonates with more common acquired conditions. The context of the diagnostic evaluation can introduce unique biases that increase the likelihood of diagnostic error. Herein is presented a framework for understanding diagnostic errors in perinatal medicine, and individual, team, and systems-based solutions for improving diagnosis learned through the implementation and administration of an undiagnosed and rare disease program.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clp.2019.10.002DOI Listing
March 2020

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

Genet Med 2020 05 17;22(5):878-888. Epub 2020 Jan 17.

Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).

Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.

Results: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners.

Conclusions: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0747-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920571PMC
May 2020

Genetic variants in DGAT1 cause diverse clinical presentations of malnutrition through a specific molecular mechanism.

Eur J Med Genet 2020 Apr 25;63(4):103817. Epub 2019 Nov 25.

Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA; Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. Electronic address:

Background: DGAT1, a gene encoding a protein involved in lipid metabolism, has been recently implicated in causing a rare nutritional and digestive disease presenting as Congenital Diarrheal Disorder (CDD). Genetic causes of malnutrition can be classified as metabolic disorders, caused by loss of a specific enzyme's function. However, disease driven by genetic variants in lipid metabolism genes is not well understood, and additional information is needed to better understand these effects.

Methods: We gathered a multi-institutional cohort of undiagnosed patients with a constellation of phenotypes presenting as malnutrition and metal ion dysregulation. Clinical Whole Exome Sequencing (WES) was performed on four patients and their unaffected parents. We prioritized genetic variants based on multiple criteria including population allele frequency and presumed inheritance pattern, and identified a candidate gene. Computational modeling was used to investigate if the altered amino acids are likely to result in a dysfunctional enzyme.

Results: We identified a multi-institutional cohort of patients presenting with malnutrition-like symptoms and likely pathogenic genomic variants within DGAT1. Multiple approaches were used to profile the effect these variants have on protein structure and function. Laboratory and nutritional intervention studies showed rapid and robust patient responses.

Conclusions: This report adds on to the database for existing mutations known within DGAT1, a gene recently implicated with CDD, and also expands its clinical spectrum. Identification of these DGAT1 mutations by WES has allowed for changes in the patients' nutritional rehabilitation, reversed growth failure and enabled them to be weaned off of total parenteral nutrition (TPN).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2019.103817DOI Listing
April 2020

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

Authors:
Magdalena Koczkowska Tom Callens Yunjia Chen Alicia Gomes Alesha D Hicks Angela Sharp Eric Johns Kim Armfield Uhas Linlea Armstrong Katherine Armstrong Bosanko Dusica Babovic-Vuksanovic Laura Baker Donald G Basel Mario Bengala James T Bennett Chelsea Chambers Lola K Clarkson Maurizio Clementi Fanny M Cortés Mitch Cunningham M Daniela D'Agostino Martin B Delatycki Maria C Digilio Laura Dosa Silvia Esposito Stephanie Fox Mary-Louise Freckmann Christine Fauth Teresa Giugliano Sandra Giustini Allison Goetsch Yael Goldberg Robert S Greenwood Cristin Griffis Karen W Gripp Punita Gupta Eric Haan Rachel K Hachen Tamara L Haygarth Concepción Hernández-Chico Katelyn Hodge Robert J Hopkin Louanne Hudgins Sandra Janssens Kory Keller Geraldine Kelly-Mancuso Aaina Kochhar Bruce R Korf Andrea M Lewis Jan Liebelt Angie Lichty Robert H Listernick Michael J Lyons Isabelle Maystadt Mayra Martinez Ojeda Carey McDougall Lesley K McGregor Daniela Melis Nancy Mendelsohn Malgorzata J M Nowaczyk June Ortenberg Karin Panzer John G Pappas Mary Ella Pierpont Giulio Piluso Valentina Pinna Eniko K Pivnick Dinel A Pond Cynthia M Powell Caleb Rogers Noa Ruhrman Shahar S Lane Rutledge Veronica Saletti Sarah A Sandaradura Claudia Santoro Ulrich A Schatz Allison Schreiber Daryl A Scott Elizabeth A Sellars Ruth Sheffer Elizabeth Siqveland John M Slopis Rosemarie Smith Alberto Spalice David W Stockton Haley Streff Amy Theos Gail E Tomlinson Grace Tran Pamela L Trapane Eva Trevisson Nicole J Ullrich Jenneke Van den Ende Samantha A Schrier Vergano Stephanie E Wallace Michael F Wangler David D Weaver Kaleb H Yohay Elaine Zackai Jonathan Zonana Vickie Zurcher Kathleen B M Claes Marica Eoli Yolanda Martin Katharina Wimmer Alessandro De Luca Eric Legius Ludwine M Messiaen

Hum Mutat 2020 01 26;41(1):299-315. Epub 2019 Oct 26.

Department of Genetics, University of Alabama at Birmingham, Birmingham, Albama.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973139PMC
January 2020

Biallelic variants in AGMO with diminished enzyme activity are associated with a neurodevelopmental disorder.

Hum Genet 2019 Dec 25;138(11-12):1259-1266. Epub 2019 Sep 25.

Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.

Alkylglycerol monooxygenase (AGMO) is the only enzyme known to cleave the O-alkyl bonds of ether lipids (alkylglycerols) which are essential components of cell membranes. A homozygous frameshift variant [p.(Glu324LysfsTer12)] in AGMO has recently been reported in two male siblings with syndromic microcephaly. In this study, we identified rare nonsense, in frame deletion, and missense biallelic variants in AGMO in two unrelated individuals with neurodevelopmental disabilities. We assessed the activity of seven disease associated AGMO variants including the four variants identified in our two affected individuals expressed in human embryonic kidney (HEK293T) cells. We demonstrated significantly diminished enzyme activity for all disease-associated variants, supporting the mechanism as decreased AGMO activity. Future mechanistic studies are necessary to understand how decreased AGMO activity leads to the neurologic manifestations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-019-02065-xDOI Listing
December 2019

Hemophagocytic lymphohistiocytosis mimicking neonatal hemochromatosis.

Pediatr Hematol Oncol 2019 Oct 19;36(7):451-456. Epub 2019 Aug 19.

Department of Pediatrics, Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Medical College of Wisconsin , Milwaukee , Wisconsin , USA.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal illness characterized by impaired natural killer (NK) cell and cytotoxic T-cell function. Patients develop systemic inflammation, multisystem organ dysfunction, and if untreated, death. Patients who present in the neonatal period often have atypical presentations with evidence of liver dysfunction and cholestasis; this has a broad differential diagnosis including neonatal infection, congenital liver defects, or other causes of liver dysfunction, such as neonatal hemochromatosis. Here, we present an infant whose diagnosis of familial HLH was confounded by the history of a stillborn sibling with suspected neonatal hemochromatosis, ultimately delaying diagnosis and initiation of curative treatment. This highlights the need to maintain a low threshold for sending HLH work-up concurrently with evaluation of liver diseases in infants with liver dysfunction, to ensure timely diagnosis and initiation of treatment. Clinicians should maintain a high index of suspicion for HLH and be aware that HLH may mimic the findings on liver biopsy seen in neonatal hemochromatosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/08880018.2019.1654051DOI Listing
October 2019

Keeping a Flexible Differential Diagnosis: an Exercise in Clinical Reasoning.

J Gen Intern Med 2019 06 7;34(6):1063-1068. Epub 2019 Mar 7.

Medicine and Pediatrics at the University of Minnesota Medical School, Minneapolis, MN, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11606-019-04867-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544697PMC
June 2019

Severe Neonatal RYR1 Myopathy With Pathological Features of Congenital Muscular Dystrophy.

J Neuropathol Exp Neurol 2019 03;78(3):283-287

Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.

The phenotypes associated with pathogenic variants in the ryanodine receptor 1 gene (RYR1, OMIM# 180901) have greatly expanded over the last few decades as genetic testing for RYR1 variants has become more common. Initially described in association with malignant hyperthermia, pathogenic variants in RYR1 are typically associated with core pathology in muscle biopsies (central core disease or multiminicore disease) and symptomatic myopathies with symptoms ranging from mild weakness to perinatal lethality. We describe a 2-week-old male patient with multiple congenital dysmorphisms, severe perinatal weakness, and subsequent demise, whose histopathology on autopsy was consistent with congenital muscular dystrophy. Immunohistochemical analysis of dystrophy-associated proteins was normal. Rapid exome sequencing revealed a novel heterozygous nonsense variant (p.Trp661Ter) in RYR1, as well as a previously described RYR1 pathogenic variant associated with congenital myopathy (p.Phe4976Leu). This highlights the potential for RYR1 pathogenic variants to produce pathological findings most consistent with congenital muscular dystrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnen/nlz004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380315PMC
March 2019

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

Am J Hum Genet 2018 12 29;103(6):1038-1044. Epub 2018 Nov 29.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address:

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288413PMC
December 2018

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Genet Med 2019 03;21(3):764-765

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.

A correction has been published to this Article. The PDF and HTML have been updated accordingly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0326-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608433PMC
March 2019

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Genet Med 2019 04 7;21(4):867-876. Epub 2018 Sep 7.

Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.

Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.

Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.

Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0269-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752285PMC
April 2019

Inheritance of a Balanced t(12;20)(q24.33;p12.2) and Unbalanced der(13)t(7;13)(p21.3;q33.2) from a Maternally Derived Double Balanced Translocation Carrier.

J Pediatr Genet 2018 Mar 14;7(1):35-39. Epub 2017 Aug 14.

Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.

We report a 4-month-old male proband with a history of prominent forehead, hypertelorism, ear abnormalities, micrognathia, hypospadias, and multiple cardiac abnormalities. Initial microarray analysis detected a concurrent 7p21.3-p22.3 duplication and 13q33.2-q34 deletion indicating an unbalanced rearrangement. However, subsequent conventional cytogenetic studies only revealed what appeared to be a balanced t(12;20)(q24.33;p12.2). Fluorescence in situ hybridization (FISH) using chromosome-specific subtelomere probes confirmed the presence of an unbalanced der(13)t(7;13)(p21.3;q33.2) and balanced t(12;20)(q24.33;p12.2), both of maternal origin. In addition to our unique clinical findings, this case highlights the benefits and limitations of both conventional cytogenetic studies and microarray analysis and how FISH complements each methodology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0037-1605592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809171PMC
March 2018

A Rare Combination of Functional Disomy Xp, Deletion Xq13.2-q28 Spanning the Gene, and Duplication 3q25.33-q29 in a Female with der(X)t(X;3)(q13.2;q25.33).

J Pediatr Genet 2018 Mar 26;7(1):23-28. Epub 2017 Jul 26.

Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.

We report a 19-year-old female patient with a history of short stature, primary ovarian insufficiency, sensorineural hearing loss, sacral teratoma, neurogenic bladder, and intellectual disability with underlying mosaicism for der(X)t(X;3)(q13.2;q25.33), a ring X chromosome, and monosomy X. Derivative X chromosomes from unbalanced X-autosomal translocations are preferentially silenced by the gene (Xq13.2) located within the X-inactivation center. The unbalanced X-autosomal translocation in our case resulted in loss of the gene thus precluding the inactivation of the derivative X chromosome. As a result, clinical features of functional disomy Xp, Turner's syndrome, and duplication 3q syndrome were observed. Importantly, indications of the derivative X chromosome were revealed by microarray analysis following an initial diagnosis of Turner's syndrome made by conventional cytogenetic studies approximately 18 months earlier. This case demonstrates the importance of utilizing microarray analysis as a first-line test in patients with clinical features beyond the scope of a well-defined genetic syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0037-1604448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809172PMC
March 2018

Inactivation of AMMECR1 is associated with growth, bone, and heart alterations.

Hum Mutat 2018 02 14;39(2):281-291. Epub 2017 Dec 14.

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23373DOI Listing
February 2018

Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics.

J Invest Dermatol 2018 04 22;138(4):957-967. Epub 2017 Nov 22.

Department of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. Electronic address:

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2017.10.033DOI Listing
April 2018

Genetic Testing Protocol Reduces Costs and Increases Rate of Genetic Diagnosis in Infants with Congenital Heart Disease.

Pediatr Cardiol 2017 Oct 19;38(7):1465-1470. Epub 2017 Jul 19.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Genetic testing is routinely performed on infants with critical congenital heart disease (CHD). This project reviewed the effect of implementing a genetic testing protocol in this population. Charts of infants with critical CHD were reviewed for genetic testing and results across two time periods: the time before implementation of a genetic testing protocol (pre-protocol) and the time after implementation (post-protocol). The use of karyotype, 22q11.2 Deletion testing, and chromosomal microarray were compared across these two time periods. Records of 891 infants were reviewed. 562 (63%) had at least one of the target genetic tests completed. During the pre-protocol time period, 66% of patients who had genetic testing underwent multiple tests versus 24% during the post-protocol time period (p < 0.01). The rate of patients who underwent genetic testing increased from 60% in the pre-protocol time period to 77% in the post-protocol time period (p < 0.01). The rate of diagnosis of genetic conditions during the pre-protocol period was 26% versus 36% during the post-protocol period (p = 0.01). There was a reduction in cost to patients by $5105.59 per diagnosis during the post-protocol period. Patients with critical CHD in the post-protocol period were less likely to undergo multiple genetic tests and more likely to have a diagnosis of genetic disease. In addition there was a significant reduction in cost per diagnosis during the post-protocol time period. Genetic testing protocols for infants with critical CHD promoted more efficient use of genetic testing and increased the rate of diagnosis of genetic conditions in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00246-017-1685-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628185PMC
October 2017

Mosaic Trisomy 9p in a Patient with Mild Dysmorphic Features and Normal Intelligence.

J Assoc Genet Technol 2017 ;43(2):56-58

Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin.

To the Editor: Partial and whole duplications of the short arm of chromosome 9 have been commonly reported in the literature with characteristic phenotypic features and intellectual disabilities. The clinical features of 9p duplications are broad and can include growth retardation, developmental delay, intellectual disability, microbrachycephaly, deep set eyes, hypertelorism, downslanting palpebral fissures, prominent nasal root, bulbous nasal tip, low-set ears, short fingers and toes with hypoplastic nails, and delayed bone age (Bonaglia et al., 2002; Zou et al., 2009; Guilherme et al., 2014).
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2017