Familial LCAT Deficiency and Low HDL-C Levels: In silico Characterization of Two Rare LCAT Missense Mutations.

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.

Novel mutation in RPGRIP1L gene causing Joubert syndrome: A case report.

INTRODUCTION: Joubert syndrome is a rare disease of genetic origin with autosomal recessive inheritance and extreme genetic heterogeneity with more than 40 causative genes. Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene. PATIENT CONCERNS: Our report describes a pediatric patient with clinical features compatible with JS type 7 such as hypotonia, developmental delay and aplasia of the cerebellar vermis. DIAGNOSIS: The clinical features and the MRI of the head and neck which showed alterations at the level of the posterior fossa, with absence of the vermis and horizontal disposition of the cerebellar peduncles, were compatible with Joubert syndrome. Whole exome sequencing detected the variants RPGRIP1L (NM_015272.2) c.697A > T (p. Lys233Ter) and RPGRIP1L (NM_015272.2) c.3545 del (p.Pro1182LeufsTer25). INTERVENTIONS: Resection was performed to correct the polydactyly. At age 2 years umbilical hernia, adenoid surgery and ventilatory tubes surgery were performed. Renal biopsy confirmed interstitial fibrosis and focally accentuated mild tubular atrophy with focal tubular hypertrophy, compatible with the clinical suspicion of Joubert syndrome. Congenital hip dislocation surgery was performed. The patient underwent surgery for correction of concomitant divergent strabismus and continued with glasses for astigmatism and hyperopia. OUTCOMES: Sanger sequencing confirmed the patient´s results and the father was found to be a carrier of RPGRIP1L (NM_015272.2) c.697A > T (p. Lys233Ter) and the mother and maternal grandmother as carriers of RPGRIP1L (NM_015272.2) c.3545del (p.Pro1182LeufsTer25). RPGRIP1L:c.3545del novel variant is a deletion which changes the reading frame, altering the RPGR1_C terminal domain and giving rise to an incomplete protein whose functions will be altered. CONCLUSION: This is the first genetically confirmed case of JS in Colombia, the first carrier of biallelic RPGRIP1L gene mutations with hip dislocation and incomplete glottic closure and the first report of the novel c.3545del likely pathogenic variant causing JS.

Frequency of polymorphisms in the CYP2C9, VKORC1, and CYP4F2 genes related to the metabolism of Warfarin in healthy donors from Cali, Colombia.

Alleles in the VKORC1, CYP2C9, and CYP4F2 genes can influence Warfarin dose requirement. We aimed to determine the frequency of the polymorphisms in these genes in healthy individuals from Cali, Colombia. Observational study where total blood was collected from 107 healthy donors who attended a higher educational institution in Cali, Colombia. Sanger sequencing of exons 2, 3, 5, and 7 of the CYP2C9 gene; the common promoter region of CYP (rs12777823); exon 11 of CPY4F2 and the polymorphism c.-1639G > A in the VKORC1 gene promoter was performed. CYP2C9*2, CYP2C9*3, CYP2C9*8, CYP2C9*9, CYP2C9*11, CYP4F2*3, rs12777823, and VKORC1*2 were detected. The latter had the highest frequency with 80 (74.8%) participants in a heterozygous or homozygous state. The least frequent allele was CYP2C9*11 with only 1 carrier. Combined haplotypes (VKORC1 *1/*2 or *2/*2 and CYP2C9 *1/*2 or *2/*2) were identified in 14 (13.7%) subjects. Both frequencies found in the VKORC1 and CYP2C9 alleles were similar to the ones reported for Latin Americans of European and Native American Ancestry. VKORC1*2 allele, the main genetic contributor to Warfarin dosing requirement, was the variant with the highest frequency (74.8% subjects, with a frequency of the alternative allele (A) of 50%). Our findings provide researchers with a greater insight regarding the frequency of common polymorphisms that affect anticoagulation treatment in the Cali (Colombia) population.

Case report: Novel frameshift mutation in LAMA2 gene causing congenital muscular dystrophy type 1A.

Congenital muscular dystrophy type 1A (CMD1A) is a rare autosomal recessive disorder caused by mutations in the LAMA2 gene. CMD1A is characterized by peripheral hypotonia and muscle weakness from the first months of life, cerebral white matter abnormalities, and elevated creatine phosphokinase (CPK) levels. We describe an 8-year-old girl from Colombia with clinical features compatible with CMD1A, severe scoliosis corrected with surgery, and feeding difficulty corrected with a gastrostomy. Whole-exome sequencing identified two heterozygous variants: a reported nonsense variant (LAMA2 NM_000426.3:c.4198C>T) and a novel likely pathogenic variant (LAMA2 NM_000426.3:c.9227_9243dup). This is the first genetically confirmed case of CMD1A in Colombia and the first report of the c.9227_9243dup variant causing CMD1A.

Hearing Loss in Patients With Morquio Syndrome: Protocol for a Scoping Review.

BACKGROUND: Mild to moderate hearing loss is common in patients with mucopolysaccharidosis (MPS) IVA. The hearing loss can be conductive, sensorineural, or mixed. However, in these patients, the mixed form is frequent, attributed to the combination of conductive and neurosensory elements, with slowly progressive evolution. Conductive hearing loss may be secondary to recurrent upper respiratory tract infections, serous otitis media, and deformities of the ear ossicles due to the accumulation of glycosaminoglycans (GAGs). Meanwhile, the sensorineural form is mainly attributed to the accumulation of GAGs in the auditory system. OBJECTIVE: The aim of this scoping review is to understand the extent and type of evidence in relation to the physiopathology, classification, epidemiology, and clinical management of hearing loss and the effect of therapy for hearing loss in patients with MPS IVA. METHODS: This scoping review includes participants across all genders and of no particular age group who are diagnosed with MPS IVA and develop hearing loss as a comorbidity. No exclusion criteria (country, language, or document type) will be applicable. The information sources will include experimental and quasi-experimental, analytical observational, observational, and qualitative studies. Unpublished literature will not be covered. Grey literature will be covered. A total of 2 independent reviewers will participate in the process of screening the literature, paper selection, and data extraction, and this process will be performed blindly. When all manuscripts have been selected, disagreements that arise between the 2 reviewers at each stage of the selection process will be resolved through discussion or with an additional reviewer. Results will be reported with descriptive statistics and information will be displayed in a diagrammatic or tabular manner, as explained in the JBI guidelines. RESULTS: The literature search was performed in November 2021 in MEDLINE, LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), the Cochrane Library, ScienceDirect, Google Scholar, and OpenGrey; a total of 780 results were retrieved. Completion of the review is expected in mid-2022. CONCLUSIONS: This scoping review will be the first to describe the extent of the information regarding the development of hearing loss in the MPS IVA population. The data gathered by this review may lead to an understanding of the grade of hearing loss in this population and allow for the assessment of possible interventions according to the disease pattern. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/32986.

A Novel Intronic KMT2D Variant as a Cause of Kabuki Syndrome: A Case Report.

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.

Molecular characterization of mucopolysaccharidosis type IVA patients in the Andean region of Colombia.

Colombia has a high prevalence of mucopolysaccharidosis (MPS) type IVA. Nevertheless, data regarding the mutation spectrum for MPS IVA in this population have not been completely characterized. Forty-seven families and 53 patients from seven different Colombian regions were tested for MPS IVA mutations. We compared the sequences with the N-acetylgalactosamine-6-sulfatase (GALNS) reference sequence NM_000512.4, and gene variants were reported. Bioinformatics analysis was performed using SWISS-MODEL. The mutant proteins were generated by homology from the wild-type GALNS 4FDJ template obtained from the PDB database, and visualization was performed using Swiss-PDBViewer and UCSF Chimera. The predictive analysis was run using different bioinformatic tools, and the deleterious annotation of genetic variants was performed using a neural network. We found that 79% and 21% of the cohort was homozygous and compound heterozygous, respectively. The most frequent mutation observed was p.Gly301Cys (78.3% of alleles), followed by p.Arg386Cys (10.4% of alleles). A novel mutation (p.Phe72Ile) was described and classified in silico as a pathogenic variant. This study reveals the mutation spectrum of MPS IVA in Colombia. The high prevalence of the p.Gly301Cys mutation suggests a founder effect of this variant in the Colombian population that causes diseases in the Andean region (via migration). These data can facilitate genetic counseling, prenatal diagnosis, and the design of therapeutic interventions.

Identification of Nontuberculous Mycobacteria in Drinking Water in Cali, Colombia.

Nontuberculous mycobacteria (NTM) are ubiquitous microorganisms naturally resistant to antibiotics and disinfectants that can colonize drinking water supply systems. Information regarding the spread of NTM in specifically South America and Colombia is limited. We aimed to identify and characterize NTM present in tap water samples from Cali, Colombia. Drinking water samples and faucet biofilm swabs were collected in 18 places, including the city's three main water treatment plants (WTPs). Filter-trapped material and eluates (0.45 µm) from swab washes were plated in 7H11 agar plates. Suspected colonies were evaluated microscopically, and NTM species were identified based on the rpoB gene. Antibiotic susceptibility testing was also performed. Fifty percent (9/18) of sampling points were positive for NTM (including two WTPs), from which 16 different isolates were identified: Mycobacterium mucogenicum (8/16), M. phocaicum (3/16), M. chelonae (2/16), M. mageritense (2/16), and M. fortuitum (1/16), all rapidly growing mycobacteria. A susceptibility profile was obtained from 68.75% (11/16) of the isolates. M. chelonae was the most resistant species. All NTM isolated are potentially responsible for human diseases; our findings might provide a baseline for exploring NTM transmission dynamics and clinical characterization, as well as potential associations between NTM species found in drinking water and isolates from patients.

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

BACKGROUND: 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. 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.

A Possible Association Between Zika Virus Infection and CDK5RAP2 Mutation.

INTRODUCTION: 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. CASE REPORT: 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. CONCLUSION: 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.

Methylation Status of GLP2R, LEP and IRS2 in Small for Gestational Age Children with and without Catch-up Growth

Objective: In small for gestational age (SGA) children, catch-up growth could be influenced by methylation of several genes involved in metabolism. Epigenetics may influence the development of metabolic diseases in adulthood. To compare the methylation of leptin (LEP), glucagon-like peptide-2 receptor (GLP2R), insulin receptor substrate-2 (IRS2) in SGA patients with and without catch-up growth. Methods: Observational prospective study of SGA children. Demographical and clinical variables were collected from clinical records and parents' questionnaire. Methylation status of LEP, IRS2, and GLP2R promoters was evaluated in DNA extracted from patient and one parent saliva samples. Results: Forty-eight SGA patients were included. Twenty-six (54.2%) had catch-up growth phenotype and 22 (45.8%) did not. The median age was 5.2 years [RIC 4.1-6.8] without difference between groups (p=0.306). The catch-up group had increased appetite (42.3% vs 9.1%, p=0.008), family history of dyslipidemia (42.3% vs 27.3%) and diabetes (34.6% vs 22.7%) compared to non-catch-up group. Catch-up patients had significantly larger waist circumference compared to non-catch-up group (median 55 cm [RIC 52-58] versus median 49.5 cm [RIC46-52]; p<0.001). LEP and GLP2R were methylated in all samples. IRS2 was methylated in 60% of SGA patients without difference between groups (p=0.520). Conclusion: There is no association between IRS2 methylation and catch-up growth among SGA patients. LEP and GLP2R were methylated in all SGA patients. Gene methylation may be implicated in metabolic disease later in life. More studies should be performed to confirm this hypothesis.

Expression of BAFF, APRIL, and cognate receptor genes in lupus nephritis and potential use as urinary biomarkers.

BACKGROUND: B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and their receptors BAFF-R, BCMA, and TACI are crucial factors for the survival of B lymphocytes. Recent evidence has also demonstrated the importance of BAFF/APRIL signaling in lupus nephritis (LN). This study evaluated the relationships between LN clinical characteristics and the urinary expression levels of BAFF, APRIL, and cognate receptors to assess their potential value as disease biomarkers. METHODS: Expression levels of these genes were assessed in urine samples collected from systemic lupus erythematosus (SLE) patients before renal biopsy using reverse transcription real-time PCR. RESULTS: Thirty-five patients with LN were included. Most of the patients were female (82.86%) with median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 15. BAFF mRNA was detectable in 28.57%, APRIL mRNA in 42.85%, BR3 mRNA in 48.57%, and TACI mRNA in 42.85% of urine samples. On the other hand, urinary (u)BCMA mRNA was not found in any sample. Urinary expression of most biomarkers was detected with greater frequency in class III and IV LN compared to class V LN. The expression level of uBR3 mRNA was correlated with SLEDAI-2K and histological activity index. CONCLUSION: Urinary expression of BAFF/APRIL signaling factors, especially TACI, APRIL, and BR3 mRNAs, may be useful biomarkers for LN.

Syndromic progressive neurodegenerative disease of infancy caused by novel variants in HIBCH: Report of two cases in Colombia.

3-Hydroxyisobutyryl-coenzyme A (CoA) hydrolase deficiency (HIBCHD; MIM: #250620) is a rare autosomal recessive inborn error of metabolism caused by a defect in the HIBCH enzyme, resulting in a deficiency of the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyric acid, a critical step in valine catabolism. This neurodegenerative disease of infancy is associated with hypotonia, developmental delay, cerebral atrophy and lesions in the basal ganglia on magnetic resonance imaging (MRI). In this study, we describe two unrelated patients with infantile-onset progressive neurodegenerative disease and mutations in HIBCH identified using whole exome sequencing (WES). In Case 1, WES revealed a novel homozygous variant in the HIBCH gene: c.808A>G (p.Ser270Gly). In Case 2, a novel compound heterozygous mutation in the HIBCH gene is described: c.808A>G (p.Ser270Gly) and c.173A>G (p. Asn58Ser). Parent analysis revealed that c.808A>G (p.Ser270Gly) was inherited from the father and c.173A>G (p. Asn58Ser) from the mother. These novel mutations were predicted as a disease-causing mutation. Plasma acylcarnitine analysis was normal in both patients. Physical examination showed similar features, such as axial hypotonia and spastic hypertonia in the legs. The first patient presented with difficult-to-treat seizures, while the second patient has not yet experienced documented seizures. In conclusion, our findings would widen the mutation spectrum of HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the correct diagnosis, treatment and integral management of patients with HIBCH deficiency.

Syndromic Intellectual Disability Caused by a Novel Truncating Variant in AHDC1: A Case Report.

Mutations in the AHDC1 gene are associated with the Xia-Gibbs syndrome (XGS), a sporadic genetic disorder characterised by developmental delay, intellectual disability, hypotonia, obstructive sleep apnoea, dysmorphic facial features, and cerebral malformations with plagiocephaly. Here we report the case of a 13-year-old Colombian female patient with a history of developmental delay, speech delay, sleep disturbances, and dysmorphic craniofacial features. The whole exome sequencing (WES) test revealed a novel de novo heterozygous frameshift mutation in AHDC1. The present case report describes the second case of mutations in AHDC1 in a Latin American patient. A literature review showed that the clinical features were similar in all reported patients. The WES test enabled the identification of the causality of this disorder characterised by high clinical and genetic heterogeneity.

A novel de novo TBX5 mutation in a patient with Holt-Oram syndrome.

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.