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22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.

Background: Congenital myopathy-13 (CMYP13), also known as Bailey-Bloch congenital myopathy and Native American myopathy (NAM), is a condition caused by biallelic missense pathogenic variants in STAC3, which encodes an important protein necessary for the excitation-relaxation coupling machinery in the muscle. Patients with biallelic pathogenic variants in STAC3 often present with congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, and susceptibility to malignant hyperthermia provoked by anesthesia. We present two unrelated cases of Bailey-Bloch congenital myopathy descendants of non-consanguineous parents, which were investigated for delayed psychomotor development and generalized weakness. To the best of our knowledge, these are the first descriptions of CMYP13 in Brazil. In both patients, we found the previously described pathogenic missense variant p.Trp284Ser in homozygosity. Conclusion: We seek to highlight the need for screening for CMYP13 in patients expressing the typical phenotype of the disease even in the absence of Lumbee Native American ancestry, and to raise awareness to possible complications like malignant hyperthermia in Bailey-Bloch congenital myopathy.

This study aims to analyze the potential impact of taking care of a child with congenital Zika virus syndrome (CZS) on the mental health of parents. Specifically, three objectives were formulated: (a) to assess the level of mental health of the parents; (b) to examine the influence of subjective well-being and fatigue as predictors of parents’ mental health; and (c) to identify the impact of sociodemographic variables on parents’ mental health. Sixty-nine mothers (Mage = 26.38; SD = 6.23) and 17 fathers (Mage = 31.41; SD = 7.57) of children diagnosed with CZS took part in this study. They answered a questionnaire containing measures of positive and negative affects, life satisfaction, fatigue, mental health, as well as sociodemographic questions. The results indicated that approximately 7% of the participants had low levels of mental health and probable emotional disorder. In addition, higher levels of fatigue and negative affects and lower levels of life satisfaction significantly predict a lower level of mental health. Finally, comparative analysis showed significant differences between fathers and mothers: mothers reported experiencing fewer positive and more negative affects, a lower level of satisfaction with life, a higher level of fatigue and worse mental health. In summary, this article presents an overview of the mental health of mothers and fathers of children with CZS and points the way to devising strategies for psychological intervention that promote the adaptation of parents to this kind of developmental disability in the family.

Dystrophinopathies are muscle diseases caused by pathogenic variants in DMD, the largest gene described in humans, representing a spectrum of diseases ranging from asymptomatic creatine phosphokinase elevation to severe Duchenne muscular dystrophy (DMD). Several therapeutic strategies are currently in use or under development, each targeting different pathogenic variants. However, little is known about the genetic profiles of northeast Brazilian patients with dystrophinopathies. We describe the spectrum of pathogenic DMD variants in a single center in northeast Brazil. This is an observational, cross-sectional study carried out through molecular-genetic analysis of male patients diagnosed with dystrophinopathies using Multiplex Ligation-dependent Probe Amplification (MLPA) followed by Next-Generation Sequencing (NGS)-based strategies. A total of 94 male patients were evaluated. Deletions (43.6%) and duplications (10.6%) were the most recurring patterns of pathogenic variants. However, small variants were present in 47.1% of patients, most of them nonsense variants (27.6%). This is the largest South American single-center case series of dystrophinopathies to date. We found a higher frequency of treatment-amenable nonsense single-nucleotide variants than most previous studies. These findings may have implications for diagnostic strategies in less-known populations, as a higher frequency of nonsense variants may mean a higher possibility of treating patients with disease-modifying drugs.

Background: Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by pathogenic variants in the HGSNAT gene. Data from large patient cohorts remain scarce, particularly in Latin America. Methods: We retrospectively analyzed clinical, biochemical, and genetic data from patients diagnosed with MPS IIIC through the MPS Brazil Network. Diagnosis was based on reduced activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), elevated urinary glycosaminoglycans (uGAGs), and/or molecular genetics tests. Results: A total of 101 patients were confirmed with MPS IIIC, representing one of the largest cohorts worldwide. Females accounted for 60% of cases. The mean age at symptom onset was 5.4 ± 3.9 years, while the mean age at diagnosis was 11.7 ± 6.9 years, reflecting a 6-year diagnostic delay. Most patients initially presented with developmental delay (82%) and facial dysmorphism (80%), whereas behavioral manifestations were less frequently identified (25%), suggesting a milder phenotype than previously reported. Genetic information was available for 28% of patients, showing recurrent alleles (c.372-2A>G, c.252dupT) and several novel mutations, which expand the mutational spectrum of the disease. Genotype–phenotype similarities with Portuguese, Italian, and Chinese cases suggest shared ancestry contributions. Regional differences included earlier diagnoses in the North of Brazil and high consanguinity rates in the Northeast region. Conclusions: This study describes the largest Brazilian cohort of MPS IIIC, documenting novel variants and regional heterogeneity. Findings highlight diagnostic delays, ancestry influences, and the urgent need for disease-modifying therapies.

Background Hepatic glycogen storage diseases (GSDs) are a group of rare genetic disorders in which glycogen cannot be metabolized to glucose in the liver because of enzyme deficiencies along the glycogenolytic pathway. GSDs are well‐recognized diseases that can occur without the full spectrum, and with overlapping in symptoms. Methods We analyzed a cohort of 125 patients with suspected hepatic GSD through a next‐generation sequencing (NGS) gene panel in Ion Torrent platform. New variants were analyzed by pathogenicity prediction tools. Results Twenty‐seven new variants predicted as pathogenic were found between 63 variants identified. The most frequent GSD was type Ia (n = 53), followed by Ib (n = 23). The most frequent variants were p.Arg83Cys (39 alleles) and p.Gln347* (14 alleles) in G6PC gene, and p.Leu348Valfs (21 alleles) in SLC37A4 gene. Conclusions The study presents the largest cohort ever analyzed in Brazilian patients with hepatic glycogenosis. We determined the clinical utility of NGS for diagnosis. The molecular diagnosis of hepatic GSDs enables the characterization of diseases with similar clinical symptoms, avoiding hepatic biopsy and having faster results. The study presents the largest cohort ever analyzed in Brazilian patients with hepatic glycogenosis. Thirty new mutations predicted as pathogenic were found in the 65 variants identified. We determined the clinical utility of next‐generation sequence (NGS) for diagnosis. The molecular diagnosis of hepatic GSDs enables the characterization of diseases with similar clinical symptoms, avoiding hepatic biopsy and having faster results.

TORCH: Acronym for toxoplasmosis other infections (syphilis, varicella-zoster, parvovirus b19), rubella, cytomegalovirus and herpes infections

This study describes genomic findings among individuals with both orofacial clefts (OC) and microphthalmia/anophthalmia/coloboma (MAC) recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole Exome Sequencing (WES) were performed in 17 individuals with OC-MAC. Clinical interpretation of molecular findings was based on data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them with variants in the CHD7 gene, and the others with variants in the TFAP2A , POMT1 , PTPN11 , and TP63 genes with the following syndromes: CHARGE, CHD7 -spectrum, Branchiooculofacial, POMT1 -spectrum, LEOPARD, and ADULT. Variants of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function, including DYNC2H1 , KIAA0586 , WDR34 , INTU , RPGRIP1L , KIF7 , and LMNA . These results show that WES was the most effective molecular approach for OC-MAC in this cohort. This study also reinforces the genetic heterogeneity of OC-MAC, and the importance of genes related to ciliopathies in this phenotype.

Background The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019. Results The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF. Conclusion This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services.

Objective The study aimed to evaluate the quality of life (QoL) of caregivers of children diagnosed with CZS and to assess the association of findings with socioeconomic and CZS-associated variables. Methods This was a cross-sectional, quantitative study, carried out over three days of multidisciplinary care for patients with CZS. Sixty-four participants underwent a quality of life assessment using the World Health Organization Quality of Life questionnaire (WHOQOL-BREF) in Portuguese. Results Both groups of caregivers attributed regular scores for Global QoL, and all WHOQOL-BREF domains. Among caregivers of children with CZS, QoL correlated with three of the four WHOQOL-BREF domains (psychological health: rho = 0.49, p < 0.001; social relationships: rho = 0.28, p  < 0.023; and environment: rho = 0.11, p  < 0.006), while general health perception correlated with three other domains (physical health: rho = 0.49, p  < 0.001; psychological health: rho = 0.31, p  < 0.012; and social relationships: rho = 0.30, p  < 0.016). The environment domain was associated with the level of education in this population ( p  < 0.001). Macular scarring and focal pigmentary retinal mottling were significantly associated with the physical environment ( p  = 0.039), negative feelings ( p  = 0.035), support and social aid ( p  = 0.020). Conclusion The present study demonstrates that the WHOQOL-BREF is an effective method to evaluate the general perception of QoL among caregivers of children with CZS. Our results also suggest that caregivers of children with CZS do not experience a reduced quality of life compared to caregivers of typically developing children. Significance “What is known about this topic?” The impact of this syndrome on quality of life of caretakers has not been previously evaluated. Most studies published to date with the population of caregivers of children with congenital Zika syndrome focus solely on measures of stress, parental stress, anxiety and depression. “What this paper adds?” Our findings demonstrate the influence of family income, education level and caregiver gender on their perception of quality of life. We also observed that, among the halmark symptoms present in children with congenital Zika syndrome, ocular manifestations had the greatest impact on caregivers’ quality of life.