Publications by authors named "Damara Ortiz"

13 Publications

  • Page 1 of 1

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

J Clin Invest 2021 Mar;131(5)

Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.
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http://dx.doi.org/10.1172/JCI142148DOI Listing
March 2021

Newborn Screening for Pompe Disease: Pennsylvania Experience.

Int J Neonatal Screen 2020 Nov 13;6(4). Epub 2020 Nov 13.

Department of Pediatrics, Division of Biostatistics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.
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http://dx.doi.org/10.3390/ijns6040089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712483PMC
November 2020

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.

Genet Med 2021 Feb 11;23(2):384-395. Epub 2020 Nov 11.

Institute of Human Genetics, Technical University Munich, Munich, Germany.

Purpose: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome).

Methods: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers.

Results: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined.

Conclusion: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
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http://dx.doi.org/10.1038/s41436-020-00993-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862064PMC
February 2021

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study.

Mol Genet Metab 2020 Sep - Oct;131(1-2):219-228. Epub 2020 Aug 15.

Department of Nephrology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.
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http://dx.doi.org/10.1016/j.ymgme.2020.07.007DOI Listing
August 2020

Copy number alterations involving 59 ACMG-recommended secondary findings genes.

Clin Genet 2020 Dec 10;98(6):577-588. Epub 2020 Oct 10.

Department of Pathology, University of California San Francisco, San Francisco, California, USA.

In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single-nucleotide variants (SNVs) are observed in one of 59 genes associated with a life-threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medically-actionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing. We retrospectively reviewed the CMA results to identify patients with CNVs comprising genes included in the 59-ACMG list of secondary findings. We evaluated the clinical significance of these CNVs in respect to pathogenicity, phenotypic manifestations, and heritability. We identified 23 patients (0.26%) with relevant CNV either deletions comprising the entire gene or intragenic alterations involving one or more secondary findings genes. A number of patients and/or their family members with pathogenic CNVs manifest or expected to develop an anticipated clinical phenotype and would benefit from preventive management similar to the patients with pathogenic SNVs. To improve patients' care standardization should apply to reporting of both sequencing and CNVs obtained via clinical genome-wide analysis, including chromosomal microarray and exome/genome sequencing.
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http://dx.doi.org/10.1111/cge.13852DOI Listing
December 2020

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Am J Hum Genet 2020 06 21;106(6):830-845. Epub 2020 May 21.

Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Centre Hospitalier Universitaire Toulouse, Service de Génétique Médicale, 31000 Toulouse, France. Electronic address:

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273536PMC
June 2020

Primrose syndrome: Characterization of the phenotype in 42 patients.

Clin Genet 2020 06 20;97(6):890-901. Epub 2020 Apr 20.

Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
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http://dx.doi.org/10.1111/cge.13749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384157PMC
June 2020

Partial 5p Deletion and Partial 5q Duplication in a Patient with Multiple Congenital Anomalies: A Two-Step Mechanism in Chromosomal Rearrangement Mediated by Non-Allelic Homologous Recombination.

Cytogenet Genome Res 2018 Oct 5. Epub 2018 Oct 5.

We describe a 5-month-old female who presented with clinical features of 5p deletion syndrome, including high-pitched cry, microcephaly, micrognathia, bilateral preauricular tags, bifid uvula, abnormal palmar creases, bilateral hypoplastic nipples, feeding difficulties, and developmental delay. In addition, the patient also had a cardiac defect, proximal esophageal atresia, and distal tracheoesophageal fistula. aCGH of the patient revealed a 22.9-Mb deletion of chromosome 5p15.33p14.3 and an 8.28-Mb duplication of chromosome 5q12.1q13.2. Parental chromosome analysis indicated that these alterations are de novo. Chromosome and FISH analysis demonstrated that the 5q12.1q13.2 duplicated segment was attached to the 5p14.3 region with the band 5q12.1 more distal to the centromere than the band 5q13.2. Based on the bioinformatic analysis, we postulate a mechanism for the formation of this complex rearrangement of chromosome 5 by 2-step-wise events mediate by nonallelic homologous recombination between low copy repeats. To the best of our knowledge this rearrangement found in our patient has not been reported in the literature. This report demonstrates the value of chromosome analysis in conjunction with FISH and aCGH for identification of complex rearrangements which cannot be revealed by array analysis alone.
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http://dx.doi.org/10.1159/000493381DOI Listing
October 2018

IRF2BPL Is Associated with Neurological Phenotypes.

Am J Hum Genet 2018 08 26;103(2):245-260. Epub 2018 Jul 26.

Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address:

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.
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http://dx.doi.org/10.1016/j.ajhg.2018.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081494PMC
August 2018

A case of de novo NAA10 mutation presenting with eyelid myoclonias (AKA Jeavons syndrome).

Seizure 2018 Aug 19;60:120-122. Epub 2018 Jun 19.

Department of Genetics, Children's Hospital of Pittsburgh of UPMC, United States.

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http://dx.doi.org/10.1016/j.seizure.2018.06.008DOI Listing
August 2018

De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities.

Hum Genet 2018 Mar 19;137(3):257-264. Epub 2018 Mar 19.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030-3411, USA.

PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c.1918G>T (p.Glu640*), c.4502_4505delTGCC (p.Leu1501Argfs*146) and c.903_909dup (p.Pro304Thrfs*46). All three patients had global developmental delay, intellectual disability, eye and vision abnormalities, dysmorphic features, and neuropsychiatric problems. Eye abnormalities were consistent among the three patients and consisted of stellate iris pattern and iris coloboma. Additional variable clinical features included hypotonia, skeletal abnormalities, sleeping problems, and behavioral issues such as autism and anxiety. In summary, we propose that haploinsufficiency of PRR12 is associated with this novel multisystem neurodevelopmental disorder.
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http://dx.doi.org/10.1007/s00439-018-1877-0DOI Listing
March 2018