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Sebastian Ciro Acosta,1 Lorena Díaz-Ordóñez,1,2 Juan David Gutierrez-Medina,1,3 Yisther Katherine Silva-Cuero,1,2 Luis Guillermo Arango-Vélez,4,5 Andrés Octavio García-Trujillo,4,5 Harry Pachajoa1,2,6 1Centro de Investigaciones en Anomalias Congenitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia; 2Departamento de Ciencias Basicas Medicas, Facultad de Salud, Universidad Icesi, Cali, Colombia; 3Centro de Investigaciones Clinicas, Fundacion Valle del Lili, Cali, Colombia; 4Servicio de Endocrinologia, Fundacion Valle del Lili, Cali, Colombia; 5Departamento de Medicina interna, Seccion de Endocrinologia, Universidad Icesi, Cali, Colombia; 6Genetic Division, Fundacion Valle del Lili, Cali, ColombiaCorrespondence: Lorena Díaz-Ordóñez, Centro de Investigaciones en Anomalias Congenitas y Enfermedades Raras (CIACER), Universidad Icesi, Street 18 Number 122-135, Cali, Valle del Cauca, 760031, Colombia, Tel +57 602 5552334, Email lldiaz@icesi.edu.coAbstract: Mutations in the lecithin-cholesterol acyltransferase (LCAT) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229.2):c.803G>A (p.Arg268His) and LCAT (NM_000229.2):c.368G>C (p.Arg123Pro). In silico analysis of the mutations predicted the physicochemical properties of the mutated protein, causing instability and potentially decreased LCAT function. These compound mutations highlight the clinical heterogeneity of the phenotypes associated with LCAT gene mutations.Keywords: eye, LCAT, cholesterol/trafficking, genomics, VLDL, lecithin cholesterol acyltransferase deficiency, LCAT deficiency, alpha-LCAT deficiency, fish eye disease

Lisa Ximena Rodriguez-Rojas,1,2 Estephania Candelo,3,4 Harry Pachajoa,1,2,4 Juan Esteban Garcia-Robledo,3 Jose Antonio Nastasi-Catanese,1,2 Jorge Andres Olave-Rodriguez,2 Angela R Zambrano5 1Department of Human Genetics, Fundación Valle del Lili, Cali, Colombia; 2Faculty of Health Sciences, Universidad Icesi, Cali, Colombia; 3Fundación Valle del Lili, Centro de Investigaciones Clínicas, Cali, Colombia; 4Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras, Universidad Icesi, Cali, Colombia; 5Department of Hematology/Oncology, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Lisa Ximena Rodriguez-Rojas, Department of Human Genetics, Fundación Valle del Lili, Cali, 760032, Colombia, Email lisa.rodriguez@fvl.org.coBackground: Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with MUTYH mutations is MUTYH-associated polyposis, a form of familial colorectal cancer syndrome. MUTYH may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on MUTYH mutations are on Caucasian patients.Material and Methods: We analyzed a small cohort of non-Caucasian, Colombian cancer patients with MUTYH germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without MUTYH-associated polyposis.Conclusion: With this case series, we intended to provide important data for the understanding of MUTYH as a possible driver of familial cancer, even when only heterozygous mutations are found.Keywords: MUTYH mutations, familial cancer, heterozygote MUTYH mutation, Colombia

Harry Pachajoa,1,2 Sebastian Giraldo-Ocampo3 1Genetics Division, Fundación Valle del Lili, Cali, Colombia; 2Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia; 3Departamento de Microbiología, Universidad del Valle, Cali, ColombiaCorrespondence: Harry Pachajoa, Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Universidad Icesi, Calle 18 No. 122-135 Pance, Cali, Colombia, Tel +57 5552334 ext 7653, Email hmpachajoa@icesi.edu.coAbstract: Osteogenesis imperfecta (OI) is a group of genetic skeletal disorders, with a prevalence of 1 in 15,000– 20,000 births. OI type V has been described in approximately 150 cases and all patients carry the variant (c.-14C> T) in the IFITM5 gene. However, two other variants, p.S40L and p.N48S have been reported in this gene, leading to clinical phenotypes different from OI type V. Here we described a patient with multiple bone fractures, scoliosis, skull alteration (plagiocephaly), bone deformation, bone rickets, and intramedullary epithelioid osteosarcoma that bears the recently reported heterozygous variant c.143A>G (p.N48S) in the IFITM5 gene. This case supports the pathogenicity of this new variant in the IFITM5 gene and adds information regarding its clinical phenotype.Keywords: genetic skeletal disorders, IFITM5, osteogenesis imperfecta, brittle bone disease, case report

Harry Pachajoa,1– 3 Eidith Gomez-Pineda,2 Sebastian Giraldo-Ocampo,4 Juliana Lores1– 3 1Genetics Division, Fundación Valle del Lili, Cali, Colombia; 2Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia; 3Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, Colombia; 4Universidad del Valle, Cali, ColombiaCorrespondence: Harry Pachajoa, Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Universidad Icesi, Calle 18 No. 122-135 Pance, Cali, Colombia, Tel +57 5552334 ext 7653, Email hmpachajoa@icesi.edu.coAbstract: Mowat-Wilson syndrome is a rare, autosomal dominant neurodevelopmental disorder characterized by distinctive facial gestalt and intellectual disability that is often associated with microcephaly, seizures and multiple congenital anomalies, mainly heart defects. More than 350 patients and 180 genetic variants in the ZEB2 gene, have been reported with an estimated frequency of 1 per 70,000 births. Here we report a Colombian female patient with facial gestalt, intellectual disability, microcephaly, congenital heart defects, hypothyroidism and middle ear defect associated with the nonsense pathogenic variant c.2761C>T (p.Arg921Ter) in the ZEB2 gene. This case contributes to the understanding of the clinical complications and the natural history of this complex and clinically heterogeneous disorder but also to the awareness that patients with heart congenital defects and dysmorphic facies may present an underlying genetic disorder.Keywords: neurodevelopmental disorder, ZEB2, genetic disorder, multiple congenital disorder

Lina Perafan-Valdes,1,2 Sebastian Giraldo-Ocampo,3 Juliana Lores,2 Harry Pachajoa2,4 1Universidad Libre, Programa de Maestría en Epidemiología, Cali, Colombia; 2Fundación Valle del Lili, Genetics Division, Cali, Colombia; 3Universidad del Valle, Departamento de Microbiología, Cali, Colombia; 4Universidad Icesi, Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Cali, ColombiaCorrespondence: Harry Pachajoa, Fundación Valle del Lili, Genetics Division, Carrera 98 # 18-49, Cali, Colombia, Tel +57 5552334 ext 7653, Email hmpachajoa@icesi.edu.coAbstract: Neurofibromatosis type 1 is one of the most common genetic autosomal dominant disorders described, with a prevalence of 1 in 2000 to 1 in 3000 individuals. It is characterized by skin, nerves, and bone abnormalities. Non-related to NF1, hypospadias is a displacement in the urethral opening which in the majority of patients has an idiopathic cause. Here, we describe a patient with neurofibromatosis type 1, hypospadias, and unilateral cryptorchidism. The heterozygous variants c.6789_6792delTTAC, p.(Tyr2264Thrfs*5) and c.140A>G, p.(Tyr47Cys) were found in the NF1 and NR5A1 genes, respectively. This case contributes to the phenotypical characterization of patients with NF1 but also with hypospadias caused by a mutation in the NR5A1 gene, which usually leads to severe sex disorders.Keywords: tumor predisposition syndrome, cafe-au-lait macules, external genitalia development, Colombia

Sebastian Giraldo-Ocampo,1 Rafael Adrian Pacheco-Orozco,2 Harry Pachajoa2,3 1Universidad del Valle, Cali, Colombia; 2Genetics Division, Fundación Valle del Lili, Cali, Colombia; 3Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Cali, ColombiaCorrespondence: Harry Pachajoa, Genetics Division, Fundación Valle del Lili, Carrera 98 # 18-49, Cali, Colombia, Tel +57 5552334 ext 7653, Email hmpachajoa@icesi.edu.coAbstract: White–Sutton syndrome is a rare type of autosomal dominant neurodevelopmental disorder caused by mutations, mostly de novo, in the POGZ gene. No more than 120 patients have been described so far in the literature. Common clinical manifestations include intellectual disability, developmental delay, autism spectrum disorder, other behavioral abnormalities, sleeping problems, hyperactivity and visual problems. We describe a 20-year-old male patient from Colombia who presented with delayed psychomotor development, intellectual disability, obesity, sleep difficulties, hypotonia, hypogonadism, gynecomastia, visual abnormalities and several facial dysmorphisms. Genetic testing showed a novel heterozygous frameshift variant (c.3308del; p.Leu1103Profs*19) in the POGZ gene (NM_015100.3). This is the first report of a diagnosed patient with WHSUS in Colombia.Keywords: WHSUS, neurodevelopmental disorder, Colombia, case report

Erica Aristizábal,1 Lorena Diaz-Ordóñez,1 Estephania Candelo,1,2 Harry Pachajoa1,2 1Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, Universidad Icesi, Cali, Valle del Cauca, Colombia; 2Fundación Valle del Lili, Cali, Valle del Cauca, ColombiaCorrespondence: Lorena Diaz-OrdóñezCenter for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, L Building, Zip: 760031, Universidad Icesi, Cali, ColombiaTel +57 2 5552334 Ext: 8542Email lldiaz@icesi.edu.coAbstract: Kabuki syndrome (KS) is an autosomal dominant genetic disorder in which most cases are caused by de novo mutations. KS type 1 is caused by mutations in KMT2D (OMIM: #147920) and is more common. KS type 2 is caused by mutations in KDM6A (OMIM: #300867). Both genes encode proteins that modify histones and are involved in epigenetic regulation. The enzyme histone-lysine N-methyltransferase 2D, the product of KMT2D, is expressed in most adult tissues and is essential for early embryonic development. The main clinical manifestations of KS include dysmorphic facial features, such as elongated palpebral fissures, eversion of the lateral third of the lower eyelids, and short nasal columella with a broad and depressed nasal tip. Additionally, patients also present with skeletal abnormalities, dermatoglyphic features, mild-to-moderate intellectual disability, hearing loss, and postnatal growth deficiency. We describe an 11-year-old girl from Colombia, who presented with characteristic clinical signs of KS. Genetic studies showed a KMT2D intronic variant (KMT2D NM_003482.3: c.511‐2A> T) as a cause of KS.Keywords: Kabuki syndrome, coloboma, rare disease, RNA splicing, sensorineural hearing loss

Estephania Candelo,1– 3 Maria Alejandra Estrada-Mesa,4 Adriana Jaramillo,4 Carlos Humberto Martinez-Cajas,4 Julio Cesar Osorio,4 Harry Pachajoa1,2 1Congenital Abnormalities and Rare Disease Centre (CIACER), Cali, Colombia; 2Genetics Department, Fundacion Valle del Lili, Cali, Colombia; 3Centro de Investigaciones Clínicas, Fundacion Valle del Lili, Cali, Colombia; 4Institución Universitaria Colegios de Colombia (UNICOC), Cali, ColombiaCorrespondence: Estephania Candelo Email ecandelo@icesi.edu.coBackground: DiGeorge syndrome (DG) is a genetic disorder associated with 22q11 deletion. It involves various phenotypes, including craniofacial abnormalities, congenital heart disorders, endocrine dysfunction, cognitive deficits, and psychiatric disorders. Cases commonly involve multiple anomalies. However, little is known about the condition of the oral cavity in this disorder, although palate fissure, abnormal mandible, malocclusion, and tooth hypoplasia have been identified. We aimed to determine the odontological features of patients with 22q11.2 microdeletion, in relation to gingival health and oral hygiene. We report the systemic manifestations of nine patients and results of oral evaluation of two patients. In the oral examination, oral hygiene and gingivitis were evaluated.Case Presentation: In terms of the systemic manifestations, we found high frequencies of low weight and height at birth. In terms of the oral manifestations, both examined patients presented malocclusion, enamel hypoplasia, dental crowding, anodontia, and healthy periodontium.Conclusion: Although DG has been documented to involve periodontium disease, the patients in this study exhibited more dental manifestations such as enamel defects, misalignment between the teeth and the two dental arches, anodontia, and dental crowding. As such, a multidisciplinary approach combining dentistry and healthcare is recommended in this case.Keywords: DiGeorge syndrome 22q11.2 deletion, oral manifestations, facial dysmorphism, case report

Lorena Díaz-Ordóñez,1– 3 Diana Ramírez-Montaño,1– 3 Estephania Candelo,2– 4 Carolina González-Restrepo,1 Sebastián Silva-Peña,1 Carlos Arturo Rojas,5 Mario Sepulveda Copete,5 Hector Raul Echavarria,6 Harry Pachajoa1– 3 1Basic Medical Science Department, Faculty of Health Sciences, Universidad Icesi, Cali, Colombia; 2Clinical Genetic Department, Fundación Valle del Lili, Cali, Colombia; 3Research Centre in Rare Diseases and Congenital Abnormalities (CIACER), Universidad Icesi, Cali, Colombia; 4Research Centre, Fundación Valle de Lili, Cali, Colombia; 5Gastroenterology Department, Fundacion Valle del Lili, Cali, Colombia; 6Centro Medico Imbanaco, Cali, ColombiaCorrespondence: Estephania Candelo Calle 18 122-135, Cali, 76003, ColombiaTel +57 2 5552334Fax + 57 2 555 1441Email ecandelo@icesi.edu.coBackground: 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 3ʹ 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.Results: 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.Conclusion: 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.Keywords: single nucleotide polymorphism, cytochrome P450 CYP2C19, pharmacogenetics, computational biology, treatment failure, proton pump inhibitors

Harry Pachajoa,1,2 Angelica Claros-Hulbert,3,4 Ximena García-Quintero,3,4 Lina Perafan,1 Andres Ramirez,5 Andres F Zea-Vera6 1Faculty of Health Sciences, Congenital Anomalies and Rare Diseases Investigation Center (CIACER), Universidad Icesi, Cali, Colombia; 2Genetic Department, Fundacion Valle del Lili, Cali, Colombia; 3Pediatric Palliative Care Department, Fundacion Valle del Lili, Cali, Colombia; 4Clinical Investigation Center (CIC), Fundacion Valle del Lili, Cali, Colombia; 5Faculty of Health Sciences, Praxis Jessen² + Kollegen, Berlin, Germany; 6Faculty of Health Sciences, Universidad del Valle, Cali, ColombiaCorrespondence: Harry Pachajoa Tel +57 3005757597Email harry.pachajoa@fvl.org.coAbstract: Hutchinson–Gilford progeria syndrome (HGPS) is a rare congenital disease caused by mutations in the LMNA gene. Children with HGPS are phenotypically characterized by lipodystrophy, short height, low body weight, scleroderma, reduced joint mobility, osteolysis, senile facial features, and cardiovascular compromise that usually lead to death. We aimed to describe the case of a patient who reached above-average age expectancy for children with HGPS in Latin America and describe the clinical and molecular characteristics of the patient. A 14-year-old female patient was presented with progeria-compatible phenotypic characteristics. HGPS was confirmed via LMNA gene sequencing that detected a heterozygous c.1824C>T (p.Gly608Gly) mutation. The primary aim is to describe the HGPS case, the molecular gene mutation finding, and make a short review of the limited available treatment options for children with HGPS. Such as the farnesyl transferase inhibitors in conjunction with other pharmacological therapies that have insinuated improvement in health, and survival rate.Keywords: HGPS, progeria, premature aging, genetic assessment, laminopathy, treatment

Laura Torres-Canchala,1 Daniela Castaño,2 Nathalia Silva,2 Ana María Gómez,2 Alejandro Victoria,3 Harry Pachajoa4,5 1Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, Colombia; 2Newborn Intensive Care Unit, Fundación Valle del Lili, Cali, Colombia; 3Obstetrical Intensive Care Unit, Maternal-Infant Department, Fundación Valle del Lili, Cali, Colombia; 4Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras, Universidad Icesi, Cali, Colombia; 5Genetics Service, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Laura Torres-CanchalaCentro de Investigaciones Clínicas, Fundación Valle del Lili, Cali, ColombiaTel +57-331-9090 ext 4022Email laura.torres@fvl.org.coBackground: Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately 1:100,000 live births. PS has a wide range of clinical expression and severity, so early prenatal diagnosis is difficult and genetic counseling is desirable. We describe a PS newborn with her ultrasound and molecular studies.Case Report: We describe a female term newborn with cloverleaf-shaped skull, facial hypoplasia, low ears, exophthalmos and wide, broad and deviated thumbs and hallux. The patient was diagnosed by ultrasound at 29 WGA and referred to a tertiary care hospital for her follow-up. Molecular test revealed a heterozygous pathogenic variant in intron 8 of the FGFR2 gene (FGFR2: c.940– 1G>C). It was a de-novo mutation. At 17 days of life, craniosynostosis correction and a Lefort-III frontomaxillary advancement were performed.Conclusion: Pfeiffer syndrome is a devastating genetic disorder. Prenatal diagnosis according PS morphological features in prenatal ultrasound allows timely genetic counseling, early referral to third-level centers, and close follow-up in the prenatal and postnatal stages.Keywords: Pfeiffer syndrome, acrocephalosyndactylia, craniosynostosis, fibroblast growth factor receptor 2

Harry Pachajoa,1,2 Lina Perafan,1,3 Isabella Ramos,1,4 Álvaro J Escobar4 1Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Faculty of Health Sciences, Universidad Icesi, Cali, Colombia; 2Department of Medical Genetics, Fundación Valle del Lili, Cali, Colombia; 3Hospitalization Service, Fundación Valle del Lili, Cali, Colombia; 4Department of Obstetrics and Gynecology, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Harry Pachajoa Tel +57 2 331 90 90, Extension: 7486Fax +57 2 3319090Email hmpachajoa@icesi.edu.coAbstract: Trisomy 20p is a chromosomal anomaly resulting from whole or partial duplication of the short arm of chromosome 20. It is a rarely reported syndrome and it is estimated that there are only a few cases of this condition worldwide, which hampers the phenotypic characterization of this entity. Conversely, müllerian anomalies include a group of congenital malformations of the uterus, vagina, cervix, and fallopian tubes resulting from alterations in the embryological development of the müllerian ducts. We report a case of pure trisomy 20p diagnosed using array comparative genomic hybridization (CGH) accompanied by a müllerian anomaly in a female patient with abnormal growth pattern, round face, coarse hair, broad nose, long palpebral fissure, epicanthus, and megaureter.Keywords: trisomy, trisomy 20p, chromosome duplication, duplication 20p, comparative genomic hybridization, uterine anomalies

Gabriel D Pinilla-Monsalve,1,* Juliana Lores,1,2,* Harry Pachajoa,1,2 Juan D López-Ponce de León,1,3 Alejandro López,1,4 Lisa X Rodríguez-Rojas,1,2 José A Nastasi-Catanese1,2 1Faculty of Health Sciences, Universidad Icesi, Cali 760032, Colombia; 2Department of Genetics, Fundación Valle del Lili, Cali 760032, Colombia; 3Department of Cardiology, Fundación Valle del Lili, Cali 760032, Colombia; 4Department of Endocrinology, Fundación Valle del Lili, Cali 760032, Colombia*These authors contributed equally to this workCorrespondence: José A Nastasi-Catanese Cra. 98 No. 18-49, Cali 760032, ColombiaTel +57 323 514-7106Fax +57 2 3319090Email jose.nastasi@fvl.org.coAbstract: Hypertriglyceridemia is a common disease with only 2% of cases exhibiting monogenic mutations. Familial chylomicronemia syndrome (FCS) is a rare genetic condition associated with recurrent and severe episodes of pancreatitis and is mainly caused by mutations in the LPL gene, with few cases related to abnormal function of apolipoprotein C-II. This is a 50-year-old female with a past medical history of arterial hypertension, miscarriage and recurrent pancreatitis. In the last four years, her triglycerides and lipase concentration reached > 3000 mg/dL and > 700 U/L, respectively. The patient was not responsive to statins, fibrates, or tetrahydrolipstatin. A novel homozygous frameshift mutation on exon 3 of the APOC2 gene was detected, c.133_134delTC. Subsequent Sanger sequencing confirmed that three first-degree relatives were carriers of the same mutation. To the best of our knowledge, we are reporting the first Colombian patient with FCS due to an APOC2 mutation. We propose that this mutation caused recurrent hypertriglyceridemic pancreatitis.Keywords: hypertriglyceridemia, hyperlipoproteinemia type I, apolipoprotein C-II, pancreatitis

Jessica María Forero-Delgadillo,1,2 Daniela Cleves,2,3 Vanessa Ochoa,1,2 Hernando Londoño-Correa,4 Jaime Manuel Restrepo,4 José Antonio Nastasi-Catanese,4,5 Harry Pachajoa2,5 1Pediatric Nephrology Fellow, Universidad Icesi-Fundación Valle de Lili, Cali, Colombia; 2Facultad de Ciencias de la Salud, Universidad Icesi, Cali, Colombia; 3Pediatrics Resident, Universidad Icesi-Fundación Valle de Lili, Cali, Colombia; 4Pediatric Nephrology Department, Fundación Valle del Lili, Cali, Colombia; 5Clinical Genetics Department, Fundación Valle del Lili, Cali, ColombiaCorrespondence: Harry PachajoaGenetics Division, Fundación Valle del Lili, Carrera 98 # 18-49, Cali, Valle del Cauca, ColombiaTel +57 2 3319090Email hmpachajoa@icesi.edu.coIntroduction: X-linked hypophosphatemic rickets is part of a larger group of hereditary diseases characterized by renal phosphate loss, which causes growth disorders, rickets, and osteomalacia. These conditions are characterized by disorders in phosphate equilibrium, which is essential for bone formation.Case Report: A female patient presented with bone deformities of the inferior extremities, prominent joints, and loss of teeth. She received initial management with oral calcium and orthotics in inferior extremities, with poor clinical outcome. PHEX gene sequencing revealed a pathogenic variant c.1601C>T (p.Pro534Leu).Discussion: XLHR is caused by mutations in the PHEX gene; to date, more than 460 mutations have been associated with the disease. Clinically, it is characterized by bowing of the lower extremities, decreased growth, musculoskeletal complaints, dental abscesses, and other clinical signs and symptoms of rickets.Keywords: XLHR, Phex gene, Colombia, pediatric, rickets

Estephania Candelo,1,2 Gabriela Caicedo,1 Fernando Rosso,3 Adriana Ballesteros,4 Jaime Orrego,4 Luis Escobar,5 Pablo Lapunzina,6,7 Julían Nevado,6,7 Harry Pachajoa1,81Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, Universidad Icesi, Cali, Colombia; 2MSc Biomaterials and Tissues Engineering and Genetics of Human Diseases, University College London, London, UK; 3Infectology Department, Fundación Valle del Lili, Cali, Colombia; 4Neonatal Department, Fundacion Valle del Lili, Cali, Colombia; 5Pathology Department, Fundacion Valle del Lili, Cali, Colombia; 6Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario La Paz, Madrid, 28046, Spain; 7CIBER de Enfermedades Raras (CIBERER), Madrid, ISCIII, Spain; 8Genetics Department, Fundacion Valle del Lili, Cali, ColombiaIntroduction: Zika virus (ZIKV) is a little-known emerging mosquito-borne flavivirus. The perinatal ZIKV infection was associated with birth defects during the Brazilian outbreak. There was an increased risk of intrauterine transmission of the virus and a marked increase in the number of newborns with microcephaly. We report on two such cases.Case Report: The first case was a 25-year-old pregnant woman from Colombia who became acutely ill with general symptoms during the tenth week of gestation, followed by severe generalized itching and maculopapular rash for approximately five days. This case was reported during the epidemic stage of the ZIKV infection in Colombia. At 23.3 gestational weeks, ultrasonography showed abnormal intracranial anatomy with cerebral ventriculomegaly, microcephaly, and parenchymal calcification. Given the grave prognosis, the patient elected to terminate the pregnancy at 25 gestational weeks. The second case was a 24-year-old pregnant woman who became acutely ill during the 17th week of gestation, which corresponded with the ZIKV epidemic in Colombia. At 30.5 gestational weeks, ultrasonography showed isolated fetal cerebral ventriculomegaly. We detected ZIKV in the amniotic fluid; however, the virus was not detected in the urine or serum of the mother or fetus. Tests for dengue virus, chikungunya virus, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, HIV, hepatitis B and C, and parvovirus B19 were all negative. Different samples obtained from the placenta, amniotic liquid, and cerebrospinal fluid were positive for viral isolation of ZIKV RNA using TaqMan RT-PCR. Additionally, the parents and fetuses were tested for genetic diseases using whole exome sequencing and array CGH to rule out possible genetic syndromes that produce these congenital abnormalities.Conclusion: These were the first cases in Colombia to show early vertical transmission of ZIKV and the first cases associated with congenital cerebral abnormalities in which molecular, infectious, and genomic tests were performed.Keywords: Colombia, microcephaly, whole exome sequencing, Zika virus infection, vertical transmission, brain abnormalities

Lady J Ríos-Serna,1 Lorena Díaz-Ordoñez,1 Estephania Candelo,1,2 Harry Pachajoa1,3 1Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, Universidad Icesi, Cali, Valle del Cauca, Colombia; 2Biomaterial and Tissues Engineering and Genetic of Human Diseases, University College London, London, UK; 3Fundación Valle del Lili, Cali, Valle del Cauca, Colombia Abstract: Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterized by congenital cardiac defects and congenital deformities of the upper limbs. Herein, we report the case of a 2-year-old patient presenting with clinical diagnostic criteria of HOS with interatrial and interventricular communication associated with hip dysplasia and upper limb reduction composed of radial ray anomaly. A novel de novo, potentially pathogenic variant in the TBX5 gene at NM_181486.2:c.243-1G>C was identified. Keywords: Holt-Oram syndrome, heart-hand syndrome, de novo mutation, TBX5.i>

Sara Vanegas,1 Luz Fernanda Sua,2 Jaime López-Tenorio,3 Diana Ramírez-Montaño,1 Harry Pachajoa1,4 1Department of Basic Medical Sciences, Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Universidad Icesi, Cali, Colombia; 2Department of Pathology and Laboratory Medicine, Fundación Valle del Lili, Cali, Colombia; 3Department of Obstetrics and Perinatology, Fundación Valle del Lili, Cali, Colombia; 4Department of Pediatric Medical Genetics, Fundación Valle del Lili, Cali, Colombia Background: Achondrogenesis type IA (ACG1A) is a rare, lethal autosomal recessive chondrodysplasia affecting endochondral bone ossification and differentiation, causing intrauterine growth restriction, narrow thorax, and short limbs. Mutations in TRIP11, which encodes Golgi microtubule-binding protein 210 in the Golgi apparatus, alter protein transport in tissues. Case presentation: A 28-week gestation male fetus was diagnosed with ACG1A by clinical, radiological, histologic, and molecular findings. Results: Whole exome sequencing was performed on fetal DNA and parental blood. Two fetal heterozygous novel variants of TRIP11, c.2304_2307delTCAA (p.Asn768Lysfs*7) and c.2128_2129delAT (p.lle710Cysfs*19), were inherited from the mother and father, respectively. Both variants created a reading frameshift leading to a premature stop codon and loss of protein function. Conclusion: To our knowledge, this is the first Latin American report with clinical, radiographic, and molecular diagnosis of ACG1A. Clinical and molecular diagnosis in utero is essential for genotype–phenotype correlation and is useful for providing better genetic counseling. Keywords: achondrogenesis type IA, endochondral bone, TRIP11, GMAP-210

Sandra M Tapiero-Rodriguez,1 Johanna C Acosta Guio,1 Gloria Liliana Porras-Hurtado,2 Natalia García,3 Martha Solano,4 Harry Pachajoa,5 Harvy M Velasco1 1Universidad Nacional de Colombia, Departamento de morfología, Maestría de genética humana, Bogotá, 2Family Compensation Fund of Risaralda, Pereira, 3Faculty of Medicine, Manizales University, Manizales, 4Department of Neuropediatrics, Cardioinfantil Foundation, Bogotá, 5Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras, Universidad ICESI y Fundación Valle del Lili, Cali, Colombia Background: As mucopolysaccharidosis IVA (MPS IVA) is the most frequent MPS in Colombia, this paper aims to describe its clinical and mutational characteristics in 32 diagnosed patients included in this study. Methods: Genotyping was completed by amplification and Sanger sequencing of the GALNS gene. The SWISS-model platform was used for bioinformatic analysis, and mutant proteins were generated by homology from the wild-type GALNS code 4FDI template from the Protein Data Bank (PDB) database. Docking was performed using the GalNAc6S ligand (PubChem CID: 193456) by AutoDock Vina 1.0 and visualized in PyMOL and LigPlot+. Results: Eleven variants were identified, and one new pathogenic variant was described in the heterozygous state, which is consistent with genotype c. 319 G>T or p.Ala107Ser. The pathogenic variant c.901G>T or p.Gly301Cys was the most frequent mutation with 51.6% of alleles. Docking revealed affinity energy of −5.9 Kcal/mol between wild-type GALNS and the G6S ligand. Some changes were evidenced at the intermolecular interaction level, and affinity energy for each mutant decreased. Conclusion: Clinical variables and genotypic analysis were similar to those reported for other world populations. Genotypic data showed greater allelic heterogeneity than those previously reported. Bioinformatics tools showed differences in the binding interactions of mutant proteins with the G6S ligand, in regard the wild-type GALNS. Keywords: mucopolysaccharidosis IVA, Morquio syndrome, GALNS, lysosomal storage disorder, mutation

Harry Pachajoa,1,2 William López-Quintero,3 Sara Vanegas,1 Claudia L Montoya,3 Diana Ramírez-Montaño1 1Department of Basic Medical Sciences, Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Universidad Icesi, Cali, Valle del Cauca, Colombia; 2Pediatric Medical Genetics, Fundación Valle del Lili, Cali, Valle del Cauca, Colombia; 3Dermatology Department, Fundación Valle del Lili, Cali, Valle del Cauca, Colombia Introduction: 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.Case report: 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.Conclusion: 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. Keywords: hypertrichosis, acromegaloid features, AFA syndrome, Cantú syndrome