Concordance Between Biochemical and Molecular Diagnosis Obtained by WES in Mexican Patients with Inborn Errors of Intermediary Metabolism: Utility for Therapeutic Management.

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2).

Isolated methylmalonic acidemia in Mexico: Genotypic spectrum, report of two novel MMUT variants and a possible synergistic heterozygosity effect.

Isolated methylmalonic acidemia (iMMA) is a group of monogenic metabolic disorders affecting methylmalonate and cobalamin metabolism. Five iMMA-responsible genes have been described to date: (MIM *609058), (MIM *607481, (MIM *607568), (MIM *611935), and (MIM *608419). Although iMMA is the most common form of organic acidemia reported in Mexico, its genotypic spectrum is still largely unknown.

Does the esv3587290 Copy Number Variation in the Gene Differ as a Genetic Factor for Developing Nephritis in Mexican Childhood-Onset Systemic Lupus Erythematosus Patients?

A ~3-kb deletion-type DNA copy number variation (CNV, esv3587290) located at intron 7 of the gene (1p13.1, MIM*610132) has been proposed as a genetic factor in lupus nephritis (LN) development in adult systemic lupus erythematosus (SLE) patients across European-descent populations, but its replication in other ethnicities has been inconsistent and its association with LN in childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory association study in a sample of 66 unrelated cSLE Mexican patients (11 males, 55 females; ages 7.

In Silico Structural Protein Evaluation of the Phenylalanine Hydroxylase p.(Tyr77His) Variant Associated with Benign Hyperphenylalaninemia as Identified through Mexican Newborn Screening.

Hyperphenylalaninemia (HPA), which includes phenylketonuria (PKU), is a genetic autosomal recessive disorder arising from a deficiency in the enzyme named phenylalanine hydroxylase (PAH). Affected patients can experience severe and irreversible neurological impairments when phenylalanine (Phe) blood concentration exceeds 360 μmol/L (6 mg/dL). Here, we describe a female HPA patient who was born in Mexico to Cuban non-consanguineous parents and identified by newborn screening, and who bears the previously unreported NM_000277.

Uncommon Large and Bilateral Fibrous Cephalic Plaques in a Patient with -Related Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a genetic disorder, frequently characterized by early dermatological manifestations. The recognition and adequate description of these dermatological manifestations are of utmost importance for early diagnosis, allowing for the implementation of therapeutic and preventive measures. Fibrous cephalic plaques (FCPs) are considered a major diagnostic criterion for TSC, as FCPs are the most specific skin lesions of TSC.

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis.

Trisomy X is the most frequent sex chromosome anomaly in women, but it is often underdiagnosed postnatally because most patients do not show any clinical manifestation. It is estimated that only 10% of patients with trisomy X are diagnosed by clinical findings. Thus, it has been proposed that the clinical spectrum is not yet fully delimited, and additional uncommon or atypical clinical manifestations could be related to this entity.

3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum.

The 3MC syndromes types 1-3 (MIM#257920, 265050 and 248340, respectively) are rare autosomal recessive genetic disorders caused by pathogenic variants in genes encoding the lectin complement pathway. Patients with 3MC syndrome have a distinctive facial phenotype including hypertelorism, highly arched eyebrows and ptosis. A significant number of patients have bilateral cleft lip and palate and they often exhibit genitourinary and skeletal anomalies.

The Enigmatic Etiology of Oculo-Auriculo-Vertebral Spectrum (OAVS): An Exploratory Gene Variant Interaction Approach in Candidate Genes.

The clinical diagnosis of oculo-auriculo-vertebral spectrum (OAVS) is established when microtia is present in association with hemifacial hypoplasia (HH) and/or ocular, vertebral, and/or renal malformations. Genetic and non-genetic factors have been associated with microtia/OAVS. Although the etiology remains unknown in most patients, some cases may have an autosomal dominant, autosomal recessive, or multifactorial inheritance.

Clinical, pathological, and molecular correlation of folliculocystic and collagen hamartoma: A new potential diagnostic criterion for tuberous sclerosis complex?

Folliculocystic and collagen hamartoma (FCCH) is a rare entity with only 18 reported cases worldwide. Of them, most are found in patients diagnosed with tuberous sclerosis complex (TSC). FCCH has distinctive histopathologic features, including collagen deposition in the dermis, perifollicular fibrosis, and comedones with keratin-containing cysts lined by infundibular epithelium.

Functional characterization of the p.(Gln195His) or Tainan and novel p.(Ser184Cys) or Toluca glucose-6-phosphate dehydrogenase (G6PD) gene natural variants identified through Mexican newborn screening for glucose-6-phosphate dehydrogenase deficiency.

Background: Newborn screening for glucose-6-phosphate dehydrogenase deficiency (G6PDd) was implemented in Mexico beginning in 2017. In a Mexican population, genotyping analysis of G6PD as a second-tier method identified a previously unreported missense variant, p.(Ser184Cys), which we propose to call "Toluca", and the extremely rare p.

Unusual Clinical Manifestations in a Mexican Patient with Sanfilippo B Syndrome.

We present an unusual Mexican patient affected with mucopolysaccharidosis type IIIB (MPS IIIB; also called Sanfilippo B syndrome, MIM #252920) bearing clinical features that have not previously been described for MPS IIIB (growth arrest, hypogonadotropic hypogonadism, and congenital heart disease). Chromosomal microarray analysis was useful in identifying runs of homozygosity at 17q11.1-q21.

Proposed clinical approach and imaging studies in families with oculo-auriculo-vertebral spectrum to assess variable expressivity.

A diagnosis of oculo-auriculo-vertebral spectrum (OAVS) is established when microtia is present in association with hemifacial hypoplasia (HH) and/or ocular, vertebral, and/or renal malformations. There is no consensus on which imaging studies should be used to rule out variable expressivity and distinguish "sporadic" from "familial" patients. This observational and descriptive study was performed in a Mexican population of 51 patients (32 males, 19 females, 0-18 years old) with microtia/OAVS, and their available parents.

Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the MEF2C gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype.

An Updated Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations.

Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene ( mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational spectrum in the largest cohort of HPA/PKU Mexican patients ( = 124) reported to date.

Whole-genome amplification/preimplantation genetic testing for propionic acidemia of successful pregnancy in an obligate carrier Mexican couple: A case report.

Background: Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities' current methodology for screening, which focuses on the detecting multiple genetic disorders at once. Here, we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects (PGT-M) approach for detecting propionic acidemia (PA) in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit () couple.

Case Summary: A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.

Screening of IRF6 Variants in Patients Subjected to Genetic Association Studies for Nonsyndromic Cleft Lip/Palate.

Objective: To screen for interferon regulatory factor 6 (IRF6) pathogenic variants in patients clinically diagnosed with nonsyndromic cleft lip palate (NSCL/P) and establish the proportion of misdiagnosed Van der Woude syndrome (VWS) cases, which could have biased previous NSCL/P case-control association studies.

Design: Retrospective case series.

Setting: Tertiary care children's hospital.

Nonmosaic Trisomy 19p13.3p13.2 Resulting from a Rare Unbalanced t(Y;19)(q12;p13.2) Translocation in a Patient with Pachygyria and Polymicrogyria.

Nonmosaic trisomy involving 19p13.3p13.2 is a very uncommon abnormality.

First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with Tuberous Sclerosis Complex reveals numerous novel pathogenic variants.

The aim of this study was to improve knowledge of the mutational spectrum causing tuberous sclerosis complex (TSC) in a sample of Mexican patients, given the limited information available regarding this disease in Mexico and Latin America. Four different molecular techniques were implemented to identify from single nucleotide variants to large rearrangements in the TSC1 and TSC2 genes of 66 unrelated Mexican-descent patients that clinically fulfilled the criteria for a definitive TSC diagnosis. The mutation detection rate was 94%, TSC2 pathogenic variants (PV) prevailed over TSC1 PV (77% vs.

Diagnosis of Laron syndrome using monoplex-polymerase chain reaction technology with a whole-genome amplification template: A case report.

Background: Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH) receptor (GHR), leading to GH insensitivity. LS patients typically present with severe growth retardation, obesity, and abnormal sexual maturation.

Predominance of Dystrophinopathy Genotypes in Mexican Male Patients Presenting as Muscular Dystrophy with A Normal Multiplex Polymerase Chain Reaction Gene Result: A Study Including Targeted Next-Generation Sequencing.

The complete mutational spectrum of dystrophinopathies and limb-girdle muscular dystrophy (LGMD) remains unknown in Mexican population. Seventy-two unrelated Mexican male patients (73% of pediatric age) with clinical suspicion of muscular dystrophy and no evidence of gene deletion on multiplex polymerase chain reaction (mPCR) analysis were analyzed by multiplex ligation-dependent probe amplification (MLPA). Those with a normal result were subjected to Sanger sequencing or to next-generation sequencing for plus 10 selected LGMD-related genes.

Novel Phenotypes and Cardiac Involvement Associated With DNA2 Genetic Variants.

To report two novel gene mutations causing early onset myopathy with cardiac involvement and late onset mitochondriopathy with rhabdomyolysis. We performed detailed clinical, muscle histopathology and molecular studies including mitochondrial gene NGS analysis in two patients (Patient 1 and 2), a mother and her son, belonging to a Mexican family, and a third sporadic French patient. Patient 1 and 2 presented with an early onset myopathy associated with ptosis, velopharyngeal weakness, and cardiac involvement.

Mutational spectrum of Mexican patients with tyrosinemia type 1: In silico modeling and predicted pathogenic effect of a novel missense FAH variant.

Background: Tyrosinemia type 1 (HT1, MIM#276700) is caused by a deficiency in fumarylacetoacetate hydrolase (FAH) and it is associated with severe liver and renal disfunction. At present, the mutational FAH (15q25.1, MIM*613871) spectrum underlying HT1 in the Mexican population is unknown.

Report of a patient with a de novo non-recurrent duplication of 17p11.2p12 and Yq11 deletion.

Background: The 17p11.2p12 locus is an unstable region that is predisposed to several known genomic disorders and non-recurrent rearrangements that yield varied and wide-ranging phenotypes. Nearly 1% of male newborns have deletions in the Y chromosome; these events primarily involve the heterochromatic region, but may extend to euchromatic Yq segments containing azoospermia factor regions.