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.

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.

Prevalence and risk factors for Down syndrome: A hospital-based single-center study in Western Mexico.

Although Hispanics of Mexican origin in the United States have been identified as a population with a particularly higher rate of Down syndrome (DS), there is a paucity of studies concerning this topic in Mexico. The aim of this study was to determine the prevalence and risk factors for DS in a population from Western Mexico. For prevalence, 230 liveborn infants with DS were included from a total of 89,332 births occurring during the period 2009-2017 at the Dr. Juan I. Menchaca Civil Hospital of Guadalajara (Mexico). In order to evaluate potential DS risks, a case-control study was conducted among 633 newborns, including those 211 DS patients with full trisomy 21 (cases) and 422 infants without birth defects (controls). Data were analyzed using multivariable logistic regression analysis. The overall prevalence for DS was 25.7 per 10,000 (95% confidence interval [95% CI]: 22.4-29.1). Patients with DS had a significantly higher risk for family history of DS in distant relatives (adjusted odds ratio [aOR] = 4.4, 95% CI: 2.5-7.7), relatives with thyroid disease (aOR = 2.3, 95% CI: 1.2-4.0), maternal age ≤ 19 years (aOR = 5.1, 95% CI: 2.7-9.6) or ≥ 35 years (aOR = 3.3, 95% CI: 1.5-6.9), paternal age ≤ 19 years (aOR = 3.5, 95% CI: 1.7-7.4), pre-pregnancy BMI ≥ 25 kg/m2 (aOR = 1.6, 95% CI: 1.0-2.4), and pre-pregnancy alcohol consumption (aOR = 1.8, 95% CI: 1.1-2.9). The identified risks in family history, and previously mentioned nutritional disadvantages were associated with DS in our sample and probably also to its increased prevalence in our population.

Descriptive study of the complete blood count in newborn infants with Down syndrome.

The usefulness of the complete blood count (CBC) during the first week of life in infants with Down syndrome (DS) has been recognized; however, studies are limited and have evaluated only some of the parameters of the CBC. Here, we report a prospective study of 135 infants with cytogenetically confirmed DS and a reference group of 226 infants without birth defects all born during the period 2009-2015 at the Dr. Juan I. Menchaca Civil Hospital of Guadalajara (Guadalajara, Mexico). The goal was to evaluate hematological findings in the CBC during the first 7 days of life, interpreted according to gestational and postnatal age. Data were analyzed using multivariate logistic regression analysis expressed as adjusted odds ratio (aORs) with 95% confidence intervals (95% CIs). Infants with DS had a significantly higher risk for polycythemia (aOR = 12.4, 95% CI: 4.6-33.3), macrocytosis (aOR = 15.9, 95% CI: 1.8-143.4), high values of mean corpuscular hemoglobin (aOR = 36.4, 95% CI: 4.5-294.9), anisocytosis (red blood cells of unequal size) (aOR = 3.9, 95% CI: 2.1-7.6), thrombocytopenia (aOR = 32.4, 95% CI: 15.2-68.9), white blood cell (WBC) count ≥30 × 103 /µl (aOR = 19.4, 95% CI: 4.1-91.5), lymphocytosis (aOR = 73.3, 95% CI: 9.5-565.4), and basophilia (aOR = 16.8, 95% CI: 1.9-151.5). Overall, 74% of infants with DS in our study had polycythemia, thrombocytopenia, WBC count >30 × 103 /µl, or lymphocytosis (aOR = 35.6, 95% CI: 18.8-79.2). Compared with those in other studies, our infants with DS had distinctive hematological findings including a lower frequency of thrombocytopenia, infrequent neutrophilia, and frequent lymphocytosis and neutropenia. This suggests ethnic, socioeconomic, or nutritional differences. © 2017 Wiley Periodicals, Inc.

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.

Ring chromosome 6 in a child with anterior segment dysgenesis and review of its overlap with other FOXC1 deletion phenotypes.

Here, we report a patient with ring chromosome 6 [r(6)], associated with anterior segment dysgenesis (ASD) and other anomalies. The phenotype was due to a 1880 kb microdeletion at 6p25.3 identified by whole-genome array analysis, and was mainly attributable to a FOXC1 haploinsufficiency. Currently 37 patients with r(6) have been reported. We found that facial dysmorphism, ASD, heart anomalies, brain anomalies, and hearing loss are constant features only in severe cases of r(6), mainly related to hemizygosity of FOXC1. Thus, overlaps with other FOXC1 related phenotypes, such as the 6p25 deletion syndrome, Axenfeld-Rieger syndrome type 3, and ASD type 3. Contrarily, those patients whose r(6) does not disrupt FOXC1, have mild or moderate phenotypes and do not exhibit ASD.