MTHFR 677C>T and 1298A>C Variants in Mothers of Infants with Down Syndrome from Western Mexico.

Background: Several studies in mothers of infants with Down syndrome (DS) (MoIDS) have suggested that the 677C>T and 1298A>C variants of the 5,10-methylentetrahydrofolate reductase (MTHFR) gene can increase the risk of having a child with DS. Aim: This study aimed to evaluate the MTHFR 677C>T and 1298A>C variants as potential maternal risk factors for DS. Materials and Methods: Using TaqMan allelic discrimination assay, we genotyped 95 MoIDS and 164 control mothers from western Mexico. Data were analyzed using logistic regression analysis. Results: We found that MoIDS had a significantly higher risk for the MTHFR 677TT genotype (adjusted odds ratio [aOR] = 3.4, 95% confidence interval [95% CI]: 1.1-10.6), and the MTHFR 677T allele (aOR = 1.5, 95% CI: 1.0-2.3), particularly in MoIDS <35 years of age. Conclusions: Our findings indicate that the presence of the 677TT genotype and 677T allele of the MTHFR 677C>T variant are maternal risk factors for DS in Mexican MoIDS.

TRAPPC11-CDG muscular dystrophy: Review of 54 cases including a novel patient.

The trafficking protein particle (TRAPP) complex is a multisubunit protein complex that functions as a tethering factor involved in intracellular trafficking. TRAPPC11, a crucial subunit of this complex, is associated with pathogenic variants that cause a spectrum of disease, which can range from a limb girdle muscular dystrophy (LGMD) to developmental disability with muscle disease, movement disorder and global developmental delay (GDD)/intellectual disability (ID), or even a congenital muscular dystrophy (CMD). We reviewed the phenotype of all reported individuals with TRAPPC11-opathies, including an additional Mexican patient with novel compound heterozygous missense variants in TRAPPC11 (c.751 T > C and c.1058C > G), restricted to the Latino population. In these 54 patients muscular dystrophy signs are common (early onset muscle weakness, increased serum creatine kinase levels, and dystrophic changes in muscle biopsy). They present two main phenotypes, one with a slowly progressive LGMD with or without GDD/ID (n = 12), and another with systemic involvement characterized by short stature, GDD/ID, microcephaly, hypotonia, poor speech, seizures, cerebral atrophy, cerebellar abnormalities, movement disorder, scoliosis, liver disease, and cataracts (n = 42). In 6 of them CMD was identified. Obstructive hydrocephaly, retrocerebellar cyst, and talipes equinovarus found in the individual reported here has not been described in TRAPPC11 deficiency. As in previous patients, membrane trafficking assays in our patient showed defective abnormal endoplasmic reticulum-Golgi transport as well as decreased expression of LAMP2, and ICAM-1 glycoproteins. This supports previous statements that TRAPPC11-opathies are in fact a congenital disorder of glycosylation (CDG) with muscular dystrophy.

A Family with EEC Syndrome in the Son and ADULT Syndrome in His Father Caused by the c.797G>A (p.Arg266Gln) Pathogenic Variant in the TP63 Gene.

Introduction: To our knowledge, there are few examples of intrafamilial variability involving two different TP63-linked morphopathies within a same family. Here, we describe a Mexican family in which the son had ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3), and his father acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome, both heterozygous for the p.Arg266Gln pathogenic variant in TP63. Additionally, we reviewed the clinical information reported for this TP63 genotype. Case Presentation: The son of this family presented ectodermal defects (thin and sparse hair, mild nail dysplasia), tetramelic ectrodactyly, syndactyly, and nasolacrimal duct obstruction (NLDO), indicative of an EEC3 diagnosis. His father, however, exhibited severe NLDO, facial freckling, dental abnormalities, mild nail dysplasia, and a history of micturition problems, compatible with ADULT syndrome. Both were heterozygous for the NM_003722.5(TP63):c.797G>A (p.Arg266Gln) pathogenic variant in TP63. Discussion: This report expands the spectrum of intrafamilial variability confirming that this can include the expression of distinct types of TP63-related disorders among different members of the same family, whose implications should be also considered in genetic counseling. From our review, we observed that p.Arg266Gln variant seems to correlate particularly with the presence of NLDO, sparse hair/eyebrows, ridged/dystrophic nails, anodontia/hypodontia, and micturition difficulties, as well as for a minor frequency of cleft lip/cleft palate.

MTSS2-related neurodevelopmental disorder: Further delineation of the phenotype.

MTSS2-related neurodevelopmental disorder (MTSS2-related NDD) (MIM 620086) is characterized by intellectual developmental disorder with ocular anomalies and distinctive facial features (IDDOF). The only existing report to date described five individuals who exhibited an identical de novo c.2011C>T (p.Arg671Trp) variant in the MTSS2 gene. Herein, we report a new case of MTSS2-related NND in a male dizygotic twin who presented with IDDOF and severe intellectual disability. This patient also displayed additional clinical features, including low functioning autism, hypothyroidism, duodenal obstruction secondary to Ladd's bands, inguinal hernias, cryptorchidism, transient subperiosteal new bone formation, and short stature with delayed bone age, which had not been previously reported in association with the MTSS2-related NDD. Exome sequencing identified the recurrent c.2011C>T (p.Arg671Trp) variant in the MTSS2 gene. The mother and the other twin tested negative for the pathogenic variant, while the father's participation in the study was unavailable. This case confirms that the MTSS2-related NDD is caused by the recurrent MTSS2 missense variant p.Arg671Trp. The novel findings identified in our patient expand the phenotypic spectrum associated with this new autosomal dominant entity, but further studies on its genetic and clinical manifestations are still needed.

Aneurysms involving the coronary arteries in a neonate with neurofibromatosis 1.

Aneurysmal coronary artery disease (ACAD) has been reported rarely in patients with neurofibromatosis type 1 (NF1), mostly in adults. We report on a female newborn affected by NF1 with ACAD disclosed during investigation for an abnormal prenatal ultrasound along with a review of the previously reported cases. The proposita had multiple café-au-lait spots and had no cardiac symptoms. Echocardiography, and cardiac computed tomography angiography confirmed aneurysms on the left coronary artery, left anterior descending coronary artery, and of the sinus of Valsalva. Molecular analysis detected the pathogenic variant NM_001042492.3(NF1):c.3943C>T (p.Gln1315*). Literature findings on ACAD in NF1 indicated that this mostly occurs in males, showing predilection for the development of aneurysms at the left anterior descending coronary artery, and manifesting predominantly as acute myocardial infarction, inclusively in teenagers, though it may be also asymptomatic as in our case. This report documents the first case of ACAD in a patient with NF1 diagnosed at birth, emphasizing that its early diagnosis is essential to prevent potential life-threatening events attributable directly to coronary lesions.

First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.

Introduction: PACS1-related neurodevelopmental disorder (PACS1-related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement. Case Presentation: Here, we describe 4 individuals with PACS1-related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1-related NDD. Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1-related NDD and the overlaps with WDR37- and PACS2-related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes.

Clinical insights from an unusual Turner syndrome manifestation: Congenital cutis verticis gyrata.

Cutis verticis gyrata (CVG) is classified as primary or secondary according to the absence or presence of underlying soft tissue abnormalities. We report an infant with Turner syndrome (TS) who in addition presented with CVG on the scalp. The skin biopsy revealed a hamartoma-like lesion. We reviewed the clinical and histopathological findings of the 13 reported cases of congenital CVG in patients with TS, including ours. In 11 of them, CVG was localized on the skin of the scalp, mainly on the parietal region, and in two, on the forehead. Clinically, CVG had a flesh-colored aspect, with absent or sparse hair, and was not progressive. CVG was classified as primary in four patients who had skin biopsy and it was attributed to the intrauterine lymphedema of TS. However, histopathology in two of these patients identified dermal hamartoma as a secondary cause of CVG, and in three others, including ours, there were hamartomatous changes. Although further studies are required, previous findings support the proposal that some CVG may instead be dermal hamartomas. This report alerts clinicians to recognize CVG as a low-frequency manifestation of TS, but also to consider the possible co-occurrence of TS in all female infants with CVG.

Frequency of chromosome 22q11.2 deletion among newborns with non-syndromic congenital heart defects from western Mexico.

BACKGROUND: Congenital heart defects (CHD) are among the most frequent manifestations of 22q11.2 deletion syndrome. Although we found relatively few studies aimed at specifically detecting 22q11.2 deletion in newborns (NB) with CHD, none of them has been performed in Mexico. METHODS: We conducted a prospective hospital-based study from January 2017 to March 2021 in the Genetics and Pediatric Cardiology Services of the Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, Mexico). All consecutive NBs identified with any non-syndromic major CHD confirmed by echocardiography were eligible to participate. A total of 98 NBs were included, 51 males and 47 females. Fluorescence in situ hybridization (FISH) analysis was conducted to search for deletion of chromosome 22q11.2 in interphase nuclei of standard lymphocyte cultures. RESULTS: We found eight patients (8.2%) with CHD and the 22q11.2 deletion, all of them with conotruncal defects, particularly of the truncus arteriosus (p = 0.013), tetralogy of Fallot (p = 0.024), and pulmonary atresia with ventricular septal defect (p = 0.031) subtypes. With de exception of one infant with hypocalcemia and another with hypocalcemia and thymic aplasia, the diagnosis of 22q11.2 deletion was not clinically suspected in the other patients. CONCLUSIONS: Our results confirm the importance of excluding the presence of the 22q11.2 deletion in every NB with CHDs, particularly of the conotruncal subtype, even in the absence of other manifestations.

INTRODUCCIÓN: Las cardiopatías congénitas (CC) son una de las manifestaciones más frecuentes del síndrome de deleción 22q11.2. A pesar de que existen relativamente pocos estudios dirigidos a detectar específicamente la deleción 22q11.2 en recién nacidos (RN) con CC, ninguno de ellos ha sido realizado en México. MÉTODOS: Se realizó un estudio prospectivo de base hospitalaria desde enero de 2017 hasta marzo de 2021 en los Servicios de Genética y Cardiología Pediátrica del Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, México). Todos los RN consecutivos identificados con cualquier tipo de CC mayor no sindrómica confirmada por ecocardiografía fueron elegibles para participar. Se incluyeron 98 recién nacidos, 51 de sexo masculino y 47 de sexo femenino. Mediante el análisis de hibridación fluorescente in situ (FISH, por sus siglas en inglés) se realizó la búsqueda de la deleción del cromosoma 22q11.2 en núcleos en interfase de cultivos de linfocitos estándar. RESULTADOS: Se encontraron ocho pacientes (8.2%) con CC y la deleción 22q11.2, todos ellos con defectos conotruncales, particularmente de los subtipos tronco arterioso (p = 0.013), tetralogía de Fallot (p = 0.024) y atresia pulmonar con comunicación interventricular (p = 0.031). Con excepción de un lactante con hipocalcemia y otro con hipocalcemia y aplasia tímica, el diagnóstico de deleción 22q11.2 no se sospechó clínicamente en los demás pacientes. CONCLUSIONES: Los resultados de este trabajo confirman la importancia de excluir la presencia de la deleción 22q11.2 en todos los RN con CC, particularmente del subtipo conotruncal, incluso en ausencia de otras manifestaciones.

Frequency of chromosome 22q11.2 deletion among newborns with non-syndromic congenital heart defects from western Mexico / Frecuencia de la deleción del cromosoma 22q11.2 en recién nacidos con cardiopatías congénitas no sindrómicas del occidente de México

Abstract Background: Congenital heart defects (CHD) are among the most frequent manifestations of 22q11.2 deletion syndrome. Although we found relatively few studies aimed at specifically detecting 22q11.2 deletion in newborns (NB) with CHD, none of them has been performed in Mexico. Methods: We conducted a prospective hospital-based study from January 2017 to March 2021 in the Genetics and Pediatric Cardiology Services of the Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, Mexico). All consecutive NBs identified with any non-syndromic major CHD confirmed by echocardiography were eligible to participate. A total of 98 NBs were included, 51 males and 47 females. Fluorescence in situ hybridization (FISH) analysis was conducted to search for deletion of chromosome 22q11.2 in interphase nuclei of standard lymphocyte cultures. Results: We found eight patients (8.2%) with CHD and the 22q11.2 deletion, all of them with conotruncal defects, particularly of the truncus arteriosus (p = 0.013), tetralogy of Fallot (p = 0.024), and pulmonary atresia with ventricular septal defect (p = 0.031) subtypes. With de exception of one infant with hypocalcemia and another with hypocalcemia and thymic aplasia, the diagnosis of 22q11.2 deletion was not clinically suspected in the other patients. Conclusions: Our results confirm the importance of excluding the presence of the 22q11.2 deletion in every NB with CHDs, particularly of the conotruncal subtype, even in the absence of other manifestations.

Resumen Introducción: Las cardiopatías congénitas (CC) son una de las manifestaciones más frecuentes del síndrome de deleción 22q11.2. A pesar de que existen relativamente pocos estudios dirigidos a detectar específicamente la deleción 22q11.2 en recién nacidos (RN) con CC, ninguno de ellos ha sido realizado en México. Métodos: Se realizó un estudio prospectivo de base hospitalaria desde enero de 2017 hasta marzo de 2021 en los Servicios de Genética y Cardiología Pediátrica del Hospital Civil de Guadalajara Dr. Juan I. Menchaca (Guadalajara, México). Todos los RN consecutivos identificados con cualquier tipo de CC mayor no sindrómica confirmada por ecocardiografía fueron elegibles para participar. Se incluyeron 98 recién nacidos, 51 de sexo masculino y 47 de sexo femenino. Mediante el análisis de hibridación fluorescente in situ (FISH, por sus siglas en inglés) se realizó la búsqueda de la deleción del cromosoma 22q11.2 en núcleos en interfase de cultivos de linfocitos estándar. Resultados: Se encontraron ocho pacientes (8.2%) con CC y la deleción 22q11.2, todos ellos con defectos conotruncales, particularmente de los subtipos tronco arterioso (p = 0.013), tetralogía de Fallot (p = 0.024) y atresia pulmonar con comunicación interventricular (p = 0.031). Con excepción de un lactante con hipocalcemia y otro con hipocalcemia y aplasia tímica, el diagnóstico de deleción 22q11.2 no se sospechó clínicamente en los demás pacientes. Conclusiones: Los resultados de este trabajo confirman la importancia de excluir la presencia de la deleción 22q11.2 en todos los RN con CC, particularmente del subtipo conotruncal, incluso en ausencia de otras manifestaciones.

Intrafamilial phenotypic variability in autosomal recessive DOCK6-related Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is diagnosed in presence of aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). The autosomal recessive (AR) DOCK6-related form of AOS is most often associated with a severe phenotype including also central nervous system and ocular abnormalities. We report a sister and brother with different expression of the phenotype. Both were compound heterozygous pathogenic variants in the DOCK6 gene, including a heterozygous c.5939+2T > C intronic variant that was maternally inherited, and a heterozygous deletion of exons 10 to 21 that was paternally inherited. The sister had microcephaly, periventricular calcifications, minor retinal vasculopathy, and mild impaired neurodevelopment, but only very subtle limb abnormalities and no ACC. Her brother showed a classical DOCK6-related AOS phenotype, including a severe bilateral peripheral ischemic retinopathy. From a review of 22 molecularly confirmed cases with DOCK6-related AOS with ophthalmic examination, we found that 16 of them had retinal vascular pathology (72.7%), confirming as the major ocular anomaly. Documented intrafamilial variability in our family and the evidence revised from previous reports, confirm that AR DOCK6-related AOS expressivity can produce a "milder" phenotype without ACC or TTLD, which could be underdiagnosed in simplex cases because it is difficult to recognize out of a familial context. Therefore, in order to know its real magnitude is required the future inclusion of DOCK6 gene in NGS panels directed to the study of simplex cases of patients with microcephaly, periventricular calcifications, retinal vasculopathy, and/or cardiovascular defects.

Usefulness of the MS-MLPA technique in the diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome.

INTRODUCTION: Epigenetic and genomic imprinting alterations of the 11p15.5 region cause excessive or deficient growth, which result in Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS), respectively. OBJECTIVE: To evaluate the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methylation analysis technique in the diagnosis of BWS and SRS. METHODS: 11p15.5 methylation and variants were evaluated in patients with clinical diagnosis of BWS and SRS using the MS-MLPA technique in peripheral blood DNA. RESULTS: Paternal uniparental disomy and loss of maternal IC2 methylation were identified in two patients with BWS who had omphalocele and macroglossia, respectively. Paternal IC1hypomethylation was recorded in two patients with SRS of classic phenotype. CONCLUSIONS: Adequate genotype-phenotype correlation was observed with the methylation defects that were identified, which confirms the usefulness of MLPA as a first-line study in patients diagnosed with BWS and SRS.

INTRODUCCIÓN: Las alteraciones epigenéticas y genómicas de la región improntada 11p15.5 producen crecimiento excesivo o deficiente, que se manifiesta como síndrome de Beckwith-Wiedemann o síndrome de Silver-Russell, respectivamente. OBJETIVO: Evaluar la técnica de análisis de metilación MLPA (MS-MLPA, methylation-specific multiplex ligation-dependent probe amplification) en el diagnóstico de los síndromes de Beckwith-Wiedemann y de Silver-Russell. MÉTODOS: Se evaluó la metilación y las variantes de 11p15.5 en pacientes con diagnóstico clínico de síndrome de Beckwith-Wiedemann y síndrome de Silver-Russell mediante la técnica MS-MLPA en ADN de sangre periférica. RESULTADOS: Se identificó disomía uniparental paterna y pérdida de metilación del IC2 materno en dos pacientes con síndrome de Beckwith-Wiedemann, quienes presentaron onfalocele y macroglosia, respectivamente. Se registró hipometilación paterna del IC1 en dos pacientes con síndrome de Silver-Russell de fenotipo clásico. CONCLUSIONES: Se observó adecuada correlación genotipo-fenotipo con los defectos de metilación encontrados, lo que confirma la utilidad del MLPA como estudio de primera línea en pacientes con diagnóstico de síndrome de Beckwith-Wiedemann y síndrome de Silver-Russell.

Utilidad de la técnica de MS-MLPA en el diagnóstico de los síndromes de Beckwith-Wiedemann y Silver-Russell / Usefulness of the MS-MLPA technique in the diagnosis of Beckwith-Wiedemann syndrome and Silver-Russell syndrome

Resumen Introducción: Las alteraciones epigenéticas y genómicas de la región improntada 11p15.5 producen crecimiento excesivo o deficiente, que se manifiesta como síndrome de Beckwith-Wiedemann o síndrome de Silver-Russell, respectivamente. Objetivo: Evaluar la técnica de análisis de metilación MLPA (MS-MLPA, methylation-specific multiplex ligation-dependent probe amplification) en el diagnóstico de los síndromes de Beckwith-Wiedemann y de Silver-Russell. Métodos: Se evaluó la metilación y las variantes de 11p15.5 en pacientes con diagnóstico clínico de síndrome de Beckwith-Wiedemann y síndrome de Silver-Russell mediante la técnica MS-MLPA en ADN de sangre periférica. Resultados: Se identificó disomía uniparental paterna y pérdida de metilación del IC2 materno en dos pacientes con síndrome de Beckwith-Wiedemann, quienes presentaron onfalocele y macroglosia, respectivamente. Se registró hipometilación paterna del IC1 en dos pacientes con síndrome de Silver-Russell de fenotipo clásico. Conclusiones: Se observó adecuada correlación genotipo-fenotipo con los defectos de metilación encontrados, lo que confirma la utilidad del MLPA como estudio de primera línea en pacientes con diagnóstico de síndrome de Beckwith-Wiedemann y síndrome de Silver-Russell.

Abstract Introduction: Epigenetic and genomic imprinting alterations of the 11p15.5 region cause excessive or deficient growth, which result in Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS), respectively. Objective: To evaluate the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methylation analysis technique in the diagnosis of BWS and SRS. Methods: 11p15.5 methylation and variants were evaluated in patients with clinical diagnosis of BWS and SRS using the MS-MLPA technique in peripheral blood DNA. Results: Paternal uniparental disomy and loss of maternal IC2 methylation were identified in two patients with BWS who had omphalocele and macroglossia, respectively. Paternal IC1hypomethylation was recorded in two patients with SRS of classic phenotype. Conclusions: Adequate genotype-phenotype correlation was observed with the methylation defects that were identified, which confirms the usefulness of MLPA as a first-line study in patients diagnosed with BWS and SRS.

[Genetic aspects involved in asthma]. / Aspectos genéticos implicados en el asma.

Asthma is an etiologically heterogeneous disease resulting from a complex interaction between genetic. The genetic aspects involved in asthma, which were analyzed from the perspective of the traditional model of multifactorial inheritance, were susceptibility, host factors, and environmental exposures. In the present paper, studies on their family aggregation, concordance in twins, and heritability were analized; as well as the current knowledge about candidate genes, genome wide association studies, and epigenomics contributions and other omic studies that have increased our knowledge about their pathophysiology and environmental interactions.

El asma es una patología etiológicamente heterogénea resultante de una compleja interacción entre una susceptibilidad genética, factores del huésped y exposiciones ambientales. En el presente trabajo se revisan los aspectos genéticos implicados en el asma, los cuales fueron analizados desde la perspectiva del modelo tradicional de la herencia multifactorial. Fueron incluidos los estudios sobre su agregación familiar, concordancia en gemelos y heredabilidad, así como el conocimiento actual sobre genes candidatos, estudios de asociación amplia del genoma y las recientes contribuciones de la epigenómica y otros estudios ómicos, que en conjunto han aumentado nuestro conocimiento sobre su fisiopatología e interacciones ambientales.

[Prader-Willi and Angelman syndromes: case series diagnosed by MS-MLPA assay]. / Síndromes Prader-Willi y Angelman: serie de casos diagnosticados mediante la técnica de MS-MLPA.

BACKGROUND: Prader Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders caused by deletions or methylation defects, making a loss of expression of imprinted genes located in the 15q11-q13 region, and these can be assessed by different cytogenomic and molecular techniques. We report a case series of patients with PWS and AS evaluated through the MS-MLPA assay. CLINICAL CASES: We studied four patients with a clinical diagnosis of PWS and another with AS, evaluated as far as possible with karyotype and FISH, and with MS-MLPA assay for the 15q11-q13 region in all cases. In patients with PWS, neonatal hypotonia was the main reason for consultation and in three of them we identified a deletion of 15q11-q13 by MS-MLPA, also confirmed by FISH; and in the other one, an abnormal methylation pattern consistent with a maternal uniparental disomy. The patient with AS presented with a typical picture which led to the identification of a deletion in 15q11-q13 by MS-MLPA, also confirmed by FISH. CONCLUSIONS: The use of the MS-MLPA assay for the 15q11-q13 region was very useful for the diagnosis and identification of the genomic and epigenetic defects involved in either PWS and AS.

INTRODUCCIÓN: el síndrome Prader-Willi (SPW) y el síndrome de Angelman (SA) son trastornos del neurodesarrollo producidos por deleciones o defectos de metilación que producen pérdida de expresión en los genes improntados de la región 15q11 q13, mismos que pueden ser evaluados por diferentes técnicas citogenómicas y moleculares. Presentamos una serie de pacientes con SPW y SA en los que se identificó el tipo de defecto de la región 15q11-q13 mediante la técnica de MS-MLPA. CASOS CLÍNICOS: estudiamos cuatro pacientes con diagnóstico clínico de SPW y uno con SA, evaluados en lo posible con cariotipo, FISH y todos con ensayo MS-MLPA para la región 15q11-q13. En los pacientes con SPW, la hipotonía neonatal fue el motivo principal de consulta. En tres de ellos se identificó deleción de 15q11-q13 por MS-MLPA, confirmada por FISH, y en uno el patrón de metilación anormal fue compatible con una disomía uniparental materna. El paciente con SA presentó un cuadró típico y también se identificó una deleción en 15q11-q13 por MS-MLPA, confirmada por FISH. CONCLUSIONES: confirmamos que el uso de la técnica de MS-MLPA para la región 15q11 q13 mostró ser de gran utilidad para identificar los mecanismos genómicos y epigenéticos implicados en el SPW y el SA.

MTHFR C677T and A1298C variants in Mexican Mestizo infants with neural tube defects from Western Mexico.

Our study investigated the role of MTHFR C677T and A1298C variants in infants with neural tube defects (NTDs) from western Mexico. Using TaqMan allelic discrimination assay, we genotyped 101 live-born patients with NTDs (cases) and 247 controls. Our findings do not support that homozygosity or heterozygosity for the variants C677T and A1298C in the MTHFR gene are associated with NTDs in infants. However, since we have the highest worldwide frequency of homozygotes for the MTHFR C677T variant, we cannot rule out that our propensity for NTDs may be related to how such gene variant interacts with other factors, mainly with our secular patterns of inappropriate folate intake.

Third case of Duchenne muscular dystrophy and West syndrome: Expanding the spectrum of the DMD neuropsychiatric phenotype.

Duchenne muscular dystrophy is an X-Linked neuromuscular disorder, and the most common muscular dystrophy. Neuropsychiatric phenotype associated to DMD gene mutations include now low IQ scores, epilepsy, autism, and attention deficit disorder. These have been observed with higher frequency in mutations that disrupt the short isoforms Dp71 and Dp140. West syndrome has been previously reported in two unrelated patients with Duchenne muscular dystrophy. Here, we report the third patient with West syndrome who had a novel hemizygous nonsense pathogenic variant in the exon 8 of the DMD gene c.811C>T, p.(Gln271*), suggesting West syndrome as part of the neuropsychiatric spectrum in Duchenne muscular dystrophy.

Prevalence of open neural tube defects and risk factors related to isolated anencephaly and spina bifida in live births from the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Jalisco, Mexico).

We determine the prevalence and trends of open neural tube defects (ONTDs) during 1991 to 2019 at the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Mexico). Also, details of potential risks were obtained in 662 newborns, including those 143 patients with anencephaly and open spina bifida (OSB) classified as isolated (cases) and 519 controls. Data were analyzed using multivariable logistic regression. Among 267 201 live births during the study period, 336 were born with ONTDs, yielding an overall prevalence of 12.6 per 10 000. After folic acid (FA)-related programs began in Mexico (2003-2019), only OSB showed a decline of 20.6%. For anencephaly, associated risks included relatives with neural tube defects (NTDs) (adjusted odds ratio [aOR]: 67.9, 95% confidence interval [95% CI]: 11.3-409.8), pre-pregnancy body mass index (BMI) ≥25 kg/m2 (aOR: 2.6, 95% CI: 1.1-6.0), insufficient gestational weight gain (aOR: 3.0, 95% CI: 1.3-7.1), parity ≥4 (aOR: 3.2, 95% CI: 1.3-7.7), and exposure to analgesic/antipyretic drugs (aOR: 9.0; 95% CI: 2.5-33.0). For OSB, associated risks included consanguinity (aOR: 14.0, 95% CI: 3.5-55.9), relatives with NTDs (aOR: 22.4, 95% CI: 4.5-112.9), BMI ≥25 kg/m2 (aOR: 2.5, 95% CI: 1.6-4.2), insufficient gestational weight gain (aOR: 1.9, 95% CI: 1.1-3.1), and exposures to hyperthermia (aOR: 2.3, 95% CI: 1.2-4.3), common cold (aOR: 6.8, 95% CI: 3.6-12.7), and analgesic/antipyretic drugs (aOR: 3.6, 95% CI: 1.3-10.0). Our high rate probably results from exposures to preventable risks, most related to FA, indicating a need for strengthening existing FA-related programs in Mexico.

Complete blood count differences in a cohort of Down syndrome neonates with transient abnormal myelopoiesis screened for GATA1 pathogenic variants.

Transient abnormal myelopoiesis (TAM) raises the risk for acute myeloid leukemia of Down syndrome (DS) (ML-DS), and both are related to GATA1 pathogenic variants. Here, we analyzed which findings on complete blood count (CBC) are associated with TAM in a cohort of neonates with DS screened for GATA1 pathogenic variants. The CBCs were compared among 70 newborns with DS, including 16 patients (22.9%) with TAM (cases), and 54 patients (77.1%) without TAM (controls). TAM was defined as peripheral circulating blasts (PCBs) ≥ 1%. PCR and direct sequencing were used to screen DNA samples from peripheral blood for GATA1 exon 2 mutations. Multivariate logistic regression analyses determined that the mean count of lymphocytes was significantly higher in DS infants with TAM (p = .035) and that lymphocytosis confers a risk for TAM (adjusted odds ratio = 7.23, 95% confidence intervals: 2.02-25.92). Pathogenic variants of GATA1 were identified in 2 of 70 analyzed DS neonates (2.9%), of which one had ML-DS and another had an asymptomatic TAM. Among those DS infants with TAM, the GATA1 pathogenic variant detection was 12.5%. Our results indicated that lymphocytosis is associated with TAM in neonates with DS. However, since not all infants with an abnormal CBC had TAM, and not all infants with TAM had GATA1 pathogenic variants, we emphasize that only the search for GATA1 pathogenic variants allows the proper identification of the subgroup of DS infants with a real increasing in risk for ML-DS.

Acute liver failure in a male patient with NGLY1-congenital disorder of deglycosylation.

Congenital disorder of N-linked deglycosylation (CDDG, MIM 615273) is a very rare autosomal recessive disorder caused by pathogenic variants in the NGLY1 gene. Transient transaminitis is the typical hepatic dysfunction described in these patients, but also included neonatal jaundice, hepatomegaly, splenomegaly, and steatosis. Microscopically, intrahepatic cytoplasmic inclusions and fibrosis are seen. We report a five-year-old male patient who presented a severe episode of acute liver failure (ALF). Exome sequencing identified compound heterozygous pathogenic/likely pathogenic variants in the NGLY1 gene: NM_018297.3:c.1891del, p.(Gln631Serfs*7) in exon 12 and NM_018297.3:c.531dup, p.(Asn178Glnfs*9) in exon 4. Serology for the most frequent viral hepatitis infections, autoimmune panel, and investigations for metabolic or toxic causes were also normal or negative. Hepatic disease resolved favorably after 46 days. Liver function tests and elastography remains normal after a 2-year follow-up. This is the first report of a reversible ALF among patients with NGLY1-CDDG. Although its definitive cause remains unknown, we suggest a direct relation between liver disease and mitochondrial respiratory chain damage in the context of impaired NGLY1 gene function. Further reports are required in order to know the long-term prognosis of ALF in patients with NGLY1-CDDG.