Diana Ramírez‐Montaño

Icesi University

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Harry Pachajoa

Icesi University

Estephanía Candelo

Fundación Valle del Lili

Lorena Díaz-Ordóñez

Icesi University

Sara Vanegas

Icesi University

Julián Nevado

Hospital Universitario Nuestra Señora de Candelaria

Pablo Lapunzina

Instituto de Investigación de Enfermedades Raras

Carlos Rodríguez‐Gallego

Universidad de Las Palmas de Gran Canaria

Joseph Dykes

Royal Blackburn Teaching Hospital

Radha Sundaram

Royal Alexandra Hospital

Victoria Clark

St George's Hospital

Cooperative Institutions

University of Edinburgh

234

University of Siena

204

National Institute for Health Research

188

University of Oxford

176

Roslin Institute

153

Instituto de Salud Carlos III

141

Intensive Care National Audit & Research Centre

140

University of Liverpool

138

University College London

132

NIHR Clinical Research Network

127

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A Possible Association Between Zika Virus Infection and CDK5RAP2 Mutation

Frontiers in Genetics (2021)

Estephanía Candelo Ana María Sanz Diana Ramírez‐Montaño Lorena Díaz-Ordóñez Ana María Granados

Flaviviridae family belongs to the Spondweni serocomplex, which is mainly transmitted by vectors from the Aedes genus. Zika virus (ZIKV) is part of this genus. It was initially reported in Brazil in December 2014 as an unknown acute generalized exanthematous disease and was subsequently identified as ZIKV infection. ZIKV became widespread all over Brazil and was linked with potential cases of microcephaly.We report a case of a 28-year-old Colombian woman, who came to the Obstetric Department with an assumed conglomerate of fetal abnormalities detected via ultrasonography, which was performed at 29.5 weeks of gestation. The patient presented with multiple abnormalities, which range from a suggested Arnold-Chiari malformation, compromising the lateral and third ventricles, liver calcifications, bilateral pyelocalic dilatations, other brain anomalies, and microcephaly. At 12 weeks of gestation, the vertical transmission of ZIKV was suspected. At 38.6 weeks of gestation, the newborn was delivered, with the weight in the 10th percentile (3,180 g), height in the 10th percentile (48 cm), and cephalic circumference under the 2nd percentile (31 cm). Due to the physical findings, brain magnetic resonance imaging (MRI) was performed, revealing a small and deviated brain stem, narrowing of the posterior fossa, a giant posterior fossa cyst with ventricular dilatation, a severe cortical and white matter thinning, cerebellar vermis with hypoplasia, and superior and lateral displacement of the cerebellum. In addition, hydrocephalus was displayed by the axial sequence, and the cerebral cortex was also compromised with lissencephaly. Schizencephaly was found with left frontal open-lip, and no intracranial calcifications were found. Two novel heterozygous nonsense mutations were identified using whole-exome sequencing, and both are located in exon 8 under the affection of ZIKV congenital syndrome (CZS) that produced a premature stop codon resulting in the truncation of the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) protein.We used molecular and microbiological assessments to report the initial case of vertically transmitted ZIKV infection with congenital syndrome associated with a neurological syndrome, where a mutation in the CDK5RAP2 gene was also identified. The CDK5RAP2 gene encodes a pericentriolar protein that intervenes in microtubule nucleation and centriole attachment. Diallelic mutation has previously been associated with primary microcephaly.

Microcephaly

Zika Virus

Hydranencephaly

Ventriculomegaly

10.3389/fgene.2021.530028

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Citations (4)

Facial dysmorphologies in genetic disorders: exploring the ancestry component in a Colombian population

The FASEB Journal (2022)

Neus Martínez Abadías Luis Miguel Echeverry Eidith Gómez Paula Solís Estephanía Candelo

Currently there are more than 10,000 rare diseases that affect about 7% of the world's population. Up to 40% of rare genetic disorders present craniofacial dysmorphologies, which can vary from subtle facial anomalies to severe malformations. Visual assessment of facial dysmorphology is commonly used for clinical diagnosis, patient management and treatment monitoring. However, qualitative descriptions are usually vague and quantitative approaches using craniofacial phenotypes for the diagnosis of rare diseases are based on North American and European populations, disregarding the influence of population ancestry on facial variation, as in Latin-America. In this study, we assessed facial dysmorphologies associated to three different genetic disorders (Down (DS), Morquio (MS) and Noonan syndrome (NS)) in a Latin-American population from Cali (Colombia). We recorded the coordinates of 18 facial landmarks in 2D images from 34 pediatric patients (19 DS, 8 MS, 6 NS) and 75 controls and quantified facial differences between patients and control groups using Euclidean Distance Matrix Analysis (EDMA). Comparisons between control and syndromic phenotypes indicated that individuals diagnosed with DS and MS presented the largest percentage of dysmorphologies, with respectively 56.2% and 54.9% of significantly different facial traits. In NS, the percentage decreased to 12.4%. Each syndrome presented a characteristic facial pattern. In DS, all facial structures were affected, with a 6% increase of relative distance between the eyes and a 7-10% reduction in facial height. The eyes and nose were most affected in MS, but not the mouth, with higher hypertelorism and facial reduction than in DS (9% and 8-17%). In NS, facial differences were more subtle and affected mainly the eyes and mouth, reducing the relative distance between them from 1 to 4% in patients as compared to controls. Our study provides a precise quantitative comparison of facial dysmorphologies in three genetic disorders that in the future can be compared with other world-wide populations to test whether facial traits associated to disease are altered by different evolutionary and adaptive histories of human populations.

Craniofacial abnormality

Hypertelorism

10.1096/fasebj.2022.36.s1.r5134

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Evaluation of CYP2C19 Gene Polymorphisms in Patients with Acid Peptic Disorders Treated with Esomeprazole

Pharmacogenomics and Personalized Medicine (2021)

Lorena Díaz-Ordóñez Diana Ramírez‐Montaño Estephanía Candelo Carolina González-Restrepo Sebastian Alejandro Silva Peña

CYP2C19 is a highly polymorphic gene that encodes an enzyme with the same name and whose function is associated with the metabolism of many important drugs, such as proton pump inhibitors (such as esomeprazole, which is used for the treatment of acid peptic disease). Genetic variants in CYP2C19 alter protein function and affect drug metabolism. This study aims to genotypically and phenotypically characterize the genetic variants in the CYP2C19 gene in 12 patients with acid peptic disorders and different therapeutic profiles to proton pump inhibitor (PPI) drugs. The patients were randomly selected from a controlled, randomized and blinded clinical pilot trial of 33 patients. We determined the presence and frequency of single nucleotide polymorphisms (SNPs) within exons 1-5 and 9, the intron-exon junctions, and a fragment in the 3' UTR region of the CYP2C19 gene using Sanger sequencing. Undescribed polymorphisms were analyzed by free online bioinformatics tools to evaluate the potential molecular effects of these genetic variants.We identified nine polymorphisms, six of which had no reported functions. One of these genetic variants, with a functional impact, not yet reported (p.Arg132Trp) was predicted by bioinformatic tools as potentially pathogenic. This finding suggests that p.Arg132Trp could be related to poor metabolizers of drugs metabolized by CYP2C19.We identified the genotype spectrum of variants in CYP2C19. The genotype spectrum of variants in CYP2C19 could predict the treatment response and could support to evaluate clinical efficacy in patients treated with esomeprazole.

Esomeprazole

Pharmacogenomics

Sanger sequencing

10.2147/pgpm.s285144

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Citations (3)

FKBP14 kyphoscoliotic Ehlers-Danlos Syndrome in adolescent patient: the first Colombian report

Archivos Argentinos de Pediatria (2019)

Felipe Ruiz-Botero Diana Ramírez‐Montaño Harry Pachajoa

Ehlers-Danlos syndrome (EDS) is a group of clinically and genetically heterogeneous inherited connective tissue disorders, characterized by skin hyperextensibility, poor wound healing, joint hypermobility and tissue friability.Since 1997 a new spectrum of novel rare EDS-variants has been described, among which is included the EDS kyphoscoliotic type, characterized by severe muscular hypotonia at birth, severe progressive kyphoscoliosis, osteopenia, fragile eyeballs and vascular fragility.This EDS variant is caused by mutations in the PLOD1 gene; however, a rare recessive variant that compromises the FKBP14 gene has been reported, with additional clinical findings that includes gross motor developmental delay, myopathy, hearing impairment and a normal ratio of lysyl pyridinoline to hydroxylysyl pyridinoline in urine.We report the first Colombian patient with a FKBP14 c.362dupC mutation, with clinical features that include generalized hypotonia, delayed gross motor milestones, hearing loss, early-onset progressive kyphoscoliosis, joint hypermobility and foot deformities.

Joint hypermobility

Ehlers–Danlos syndrome

Kyphoscoliosis

10.5546/aap.2019.eng.e274

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Citations (4)

DeSanto-Shinawi Syndrome: First Case in South America

Molecular Syndromology (2018)

Sara Vanegas Diana Ramírez‐Montaño Estephanía Candelo Marwan Shinawi Harry Pachajoa

Pathogenic variants in WAC are uncommon causes of developmental delay and neurobehavioral phenotypes. The clinical features associated with WAC haploinsufficiency include recognizable dysmorphic facial features that were recently delineated as DeSanto-Shinawi syndrome (DESSH; OMIM 616708). Additional clinical features include hypotonia, hearing and vision abnormalities, gastrointestinal problems, and behavioral difficulties. Here, we report a case of a 4-year-old Colombian male patient with typical dysmorphic facial features, developmental delay, hyperactivity, and recurrent respiratory infections. His immune workup revealed hypogammaglobulinemia, and clinical exome sequencing revealed a novel intronic variant in WAC (c.1437+1G>A). To the best of our knowledge, this is the first case of DESSH in South America, underlining the accumulating evidence of the significant role of WAC haploinsufficiency in neurobehavioral phenotypes. Although this report suggested the potential involvement of WAC in immune regulation, additional reports are required to confirm our observations.

Haploinsufficiency

Hypogammaglobulinemia

10.1159/000488815

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Citations (15)

Incidentalome in Neurogenetics: Pathogenic Variant of NSD1 in a Patient With Spinocerebellar Ataxia (SCA)

Frontiers in Genetics (2018)

Harvy Velasco Diana Ramírez‐Montaño

Background: Genetic studies of late-onset sporadic ataxias (>40 years of age) are not routinely indicated. For unresolved cases, next-generation sequencing (NGS) tools, such as whole-exome sequencing (WES), are available for a definitive diagnosis. Case presentation: Our patient is a woman with a usual facial phenotype and anthropometry, who developed ataxia at 45 years of age, with no relevant family history and an initial clinical approach that ruled out common aetiologies. WES was performed when the patient was 54 years old. The results identified the heterozygous pathogenic variant c.248delA (p.N83MfsX4) in the nuclear receptor-binding SET domain protein 1 (NSD1; MIM 606681) gene (related to Sotos syndrome), which was not associated with ataxia and is not related to the patient’s phenotype. Sanger sequencing of NSD1 in two different laboratories confirmed the variant. Conclusions: NGS findings generally offer valuable information that can be used for clinical decision-making. However, an incidental finding that leads to defining new clinical and bioethical actions is also possible. Consequently, the biological importance of this type of genetic “incidentalome” must be determined.

Sanger sequencing

Sotos syndrome

10.3389/fgene.2018.00086

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First Case Report of Prader–Willi-Like Syndrome in Colombia

Frontiers in Genetics (2018)

Estephanía Candelo Max M. Feinstein Diana Ramírez‐Montaño Juan F Bencomo Gómez Harry Pachajoa

Background: Prader–Willi-like syndrome (PWLS) is believed to be caused by a variety of disruptions in genetic pathways both inside and outside of the genetic region implicated in PWS. By definition, PWLS does not demonstrate mutations in the 15q11–q13 region itself. It is a rare disorder whose clinical hallmarks include hypotonia, obesity, short extremities and delayed development. This syndrome has been described in patients with 1p, 2p, 3p, 6q and 9q chromosome abnormalities and in cases with maternal uniparental disomy of chromosome 14 and fragile X syndrome. Case presentation: In the present report, we describe a 9-year-old Colombian patient who demonstrated features of PWS and was ultimately diagnosed with PWLS after genetic analysis revealed a 14.97 Mb deletion of 6q16.1–q21. Conclusions: This is the first reported case of PWLS in Colombia and represents one of the largest documented 6q21 deletions. Keywords: Prader–Willi-like syndrome, Prader–Willi-like phenotype, Prader–Willi syndrome (PWS), 6q16.1–q21 deletion, Pediatric Obesity

Genetic disorder

10.3389/fgene.2018.00098

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Citations (4)

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Nature (2023)

Erola Pairo‐Castineira Konrad Rawlik Andrew D. Bretherick Ting Qi Yang Wu

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown

Genome-wide Association Study

2019-20 coronavirus outbreak

10.1038/s41586-023-06034-3

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Citations (107)

Novel mutation in <em>ABBC9</em> gene associated with congenital hypertrichosis and acromegaloid facial features, without cardiac or skeletal anomalies: a new phenotype

The Application of Clinical Genetics (2018)

Harry Pachajoa William López-Quintero Sara Vanegas Claudia Montoya Diana Ramírez‐Montaño

Mutations in ABCC9 are associated with Cantú syndrome (CS), a very rare genetic disorder characterized by congenital hypertrichosis, acromegaloid facial appearance (AFA), cardiomegaly, and skeletal anomalies.We report an 8-year-old female patient with congenital generalized hypertrichosis and coarse facial appearance but without cardiovascular or skeletal compromise. Whole exome sequencing revealed a novel de novo heterozygous mutation in ABCC9. In addition, the genotype and phenotype of the patient were compared with those of the patients reported in the literature and with other related conditions that include AFA, hypertrichosis and AFA, and CS.This is the first report of a South-American patient with mutation in ABCC9. We propose that her phenotype is a part of a spectrum of features associated with congenital hypertrichosis and mutations in ABCC9, which differs from CS and related disorders. Whole exome sequencing enabled the identification of the causality of this disease characterized by high clinical and genetic heterogeneity.

Hypertrichosis

Exome

10.2147/tacg.s155022

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Microduplication of Xp22.31 and MECP2 Pathogenic Variant in a Girl with Rett Syndrome: A Case Report.

DOAJ (DOAJ: Directory of Open Access Journals) (2019)

Estephanía Candelo Diana Ramírez‐Montaño Harry Pachajoa

Rett syndrome (RS) is a neurodevelopmental infantile disease characterized by an early normal psychomotor development followed by a regression in the acquisition of normal developmental stages. In the majority of cases, it leads to a sporadic mutation in the MECP2 gene, which is located on the X chromosome. However, this syndrome has also been associated with microdeletions, gene translocations, and other gene mutations. A 12-year-old female Colombian patient was presented with refractory epilepsy and regression in skill acquisition (especially language with motor and verbal stereotypies, hyperactivity, and autistic spectrum disorder criteria). The patient was born to non-consanguineous parents and had an early normal development until the age of 36 months. Comparative genomic hybridization array-CGH (750K) was performed and Xp22.31 duplication was detected (6866889-8115153) with a size of 1.248 Mb associated with developmental delay, epilepsy, and autistic traits. Given the clinical criteria of RS, MECP2 sequencing was performed which showed a de novo pathogenic variant c.338C>G (p.Pro113Arg). The features of RS include intellectual disability, developmental delay, and autism. These features are associated with copy number variations (CNVs) on the X chromosome (Xp22.31 microduplication). Here we present the first reported case of simultaneous CNV and MECP2 pathogenic mutation in a patient with RS. We propose that both DNA alterations might have a synergistic effect and could lead to variable expressivity of the phenotype.

Rett Syndrome

MeCP2

Speech delay

Global developmental delay

Comparative genomic hybridization

10.30476/ijms.2019.44945

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Citations (3)