Journal of pediatric genetics最新文献

Sudden unexpected death in infants (SUDI) is a devastating event, and unfortunately occurs frequently in developing countries. The emerging molecular autopsy has added value to post-mortem investigations, where genetic variants were able to explain the unexpected demise. Many of these variants have been found in genes involved in arrythmia pathways. The aim of this study was to sequence 43 genes previously associated with cardiac arrhythmia in a selected cohort of SUDI cases ( n  = 19) in South Africa. A total of 335 variants were found among the 19 infants, of which four were novel. The variants were classified as "likely pathogenic" ( n  = 1), "variant of unknown significance" ( n  = 54), "likely benign" ( n  = 56) or "benign" ( n  = 224). The likely pathogenic variant was LMNA NM_170707.2:c.1279C > T (p.Arg427Cys) and was found in a 3-week-old male infant of African ancestry. Variants in LMNA have previously been associated with dilated cardiomyopathy, with a typical age of onset in adulthood; therefore, this may be the first report in an infant. The yield of pathogenic or likely pathogenic variants in the classic genes typically associated with channelopathies and sudden death, was less in this study compared with other settings. This finding highlights the importance of population-specific research to develop a molecular autopsy which is locally relevant.

Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the TBX6 gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known TBX6 gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sister for a total of 16 samples among 5 families. Variant interpretation was performed using SIFT, PolyPhen-2, Mutation Taster, and CADD. Four de novo variants were identified by ES and confirmed by Sanger sequencing: 1 frameshift variant ( SHISA3 ) and 3 missense variants ( AGBL5 , HDAC4 , and PDE2A ). ES also uncovered 1 homozygous variant in the MOCOS gene. All of these variants were predicted to be deleterious by SIFT, PolyPhen-2, Mutation Taster, and/or CADD. The number of de novo variants identified in this study was exactly what would be expected by chance. Additional functional studies or gathering matched patients using Gene Matcher are needed.

Syndromes causing short stature include Noonan syndrome (NS), Williams syndrome, and Silver-Russell syndrome (SRS). SRS is a primordial dwarfism with genetic heterogeneity. The SRS children present with prenatal growth retardation, neonatal hypoglycemia, feeding difficulties, physical asymmetry, with scoliosis and cardiac defect in some cases. The incidence is up to 1 in 100,000. Uniparental disomy, methylation abnormalities, and variants in some genes have been found underlying such phenotype. Growth hormone therapy has been used to improve the height gain in these patients. NS has genetic heterogeneity and most patients present with short stature with or without cardiac defect. Multiple genetic variants, mostly autosomal dominant, contribute to the phenotype. With the availability of next-generation sequencing, more and more genetic disorders causing short stature are being identified in different ethnic populations like Kabuki syndrome and Nance-Horan syndrome. Here, we present some cases of SRS and other additional syndromes with dysmorphism seen in past 5 years.

Beta-thalassemic patients require regular blood transfusion to sustain their life which leads to iron overload and causes oxidative stress. The aim of this study was to investigate the status of variants in genes including GSTM1 , GSTT1 (null/present), CT-262 (C > T) and CT-89 (A > T), glutathione peroxidase (GPx), and myeloperoxidase (MPO). The genotype studies were conducted with 200 thalassemia major (TM) patients and 200 healthy controls. Genotyping of GST gene was performed by multiplex polymerase chain reaction (PCR), whereas for CT, GPx and MPO genesvariants PCR- restriction fragment length polymorphism technique used. However, the enzyme activities were measured only in the patients group to assess the association with the genotypes. All enzyme estimations were performed by ELISA. We observed higher frequency of GSTT1 null, CT-89 (A > T), GPx1 198 (C > T) and MPO-463 (G > A) polymorphisms in TM patient than healthy controls. However, CT-262 (C > T) polymorphism was not found to be statistically significantly different between patients and controls. Our results suggest that frequency of null allele of glutathione-S-transferase is significantly high among TM patients. The other alleles CT-89 (A > T), GPx1 198 (C > T), and MPO-463 (G > A) are linked to decreased CT, GPX, and MPO enzyme activities.

This cross-sectional study aimed to observe number of marriages between relatives in São Francisco Valley municipalities and correlations between degrees of kinship and susceptibility to genetic diseases. Three hundred and nine (309) consanguineous couples were interviewed in five municipalities. The data were analyzed using SPSS (version 22), Chi-square testing, and the generalized estimating equation (GEE). In Pariconha-AL for first cousins, the results revealed significantly higher numbers of disabled children than for third cousins ( p  < 0.05). Of these, the prevalence for physical disability was significant ( χ 2 = 19.203, d f  = 4, p  = 0.001). In the cities of Glória-BA ( χ 2 = 11.652, d f  = 3, p  = 0.020) and OlhoD'água do Casado-AL ( χ 2 = 8.123, d f  = 4, p  = 0.044), physical disabilities were also significantly higher in children from unions of first-degree cousins than for other degrees of kinship. Visual impairment was more significant in first-degree cousins in Glória-BA ( χ 2 = 14.206, d f  = 3 p  = 0.007); yet among third-degree cousins, visual impairment in the municipality of Santa Brígida-BA was more prevalent ( χ 2 = 6.416, d f  = 2 p  = 0.040). Inbreeding, as revealed in the evaluated cities, reinforces the hypothesis for developing genetic diseases.

Cribriform appearance of the brain in Canavan disease is a rare finding. The two presented cases broaden the magnetic resonance imaging (MRI) phenotype wherein numerous oval, cystic structures, a few resembling dilated Virchow-Robin (VR) spaces, were noted in the centrum semiovale, periventricular, and lobar white matter producing a cribriform pattern. Besides, discrete round to oval cysts were present at the gray-white matter junctions in the second case, which were larger and appeared morphologically distinct from the VR spaces. These cysts did not elongate in any plane on imaging and were more representative of giant intramyelinic vacuoles. Genetic analysis revealed novel mutations in the aspartoacylase or ASPA gene that possibly accounts for the severe form of Canavan disease, which probably explains the imaging findings. The multicystic appearance of the white matter in Canavan disease is unusual and possibly represents two different histopathological substrates.

A 14-year-old male adolescent patient with Prader-Willi syndrome (PWS) with maternal disomy 15 was reported with rectal prolapse as only the second patient in the literature. With predisposing risk factors present for rectal damage and prolapse in this syndrome, the incidence must be higher and therefore underreported. These risk factors include skin and rectal picking, self-stimulation, altered pain sensation, decreased muscle mass, strength and physical activity with hypotonia, and gastrointestinal (GI) disturbances. Pertinent literature was reviewed and analyzed that focused on clinical features and behavior seen in PWS as underrecognized risk factors for developing rectal damage and prolapse. An illustrative case is presented as the second patient reported with PWS and a prolapsed rectum. A discussion of predisposing behavioral and clinical risk factors is presented including for self-stimulation, rectal picking, chronic constipation, decreased gut motility, reduced water intake, and a restricted diet. Although a paucity of cases do exist, physical, behavioral, and GI findings common in PWS may contribute to rectal prolapse requiring better awareness and proactive surveillance, management, and treatment protocols for patients affected with this rare obesity-related genetic disorder.

Primary distal renal tubular acidosis (dRTA) or Type 1 RTA in children is caused by a genetic defect (involved genes ATP6V0A4 , ATP6V1B1 , SLC4A1 , FOXI1 , or WDR72 ), which causes tubular transport defects characterized by an inability to appropriately acidify urine with resultant persistent hyperchloremic metabolic acidosis. Retrospective analysis of 28 children (14 males) under the age of 14 years with dRTA seen from 2010 to 2019 was reviewed, and detailed clinic records were analyzed. The clinical features, investigations, and response to treatment were recorded. The median age of the children at presentation was 30 months (range: 9.25-72 months), and the median age at onset of symptoms was 2 months. All the children had growth failure, polyuria, and polydipsia at presentation. Mean serum potassium, pH, bicarbonate, and anion gap at presentation was 2.3 ± 0.5 mmol/L, 7.22 ± 0.09, 13.28 ± 4.37 mmol/L, and 9.3 ± 2.18, respectively. Mean serum potassium, pH, bicarbonate at follow-up was 3.88 ± 0.6 mmol/L, 7.35 ± 0.06, and 20.13 ± 4.17 mmol/L, respectively. The median z-score for the weight for age and height for age at initial presentation was -4.77 (-7.68 to -3.74) and -4.21 (-5.42 to -2.37) and at follow-up was -3.35 (-5.29 to -1.55) and -3.84 (-5.36 to -1.63), respectively. Twenty-two (78.6%) children had medullary nephrocalcinosis. Four children had sensorineural hearing loss. Seven children had genetic testing done, and six had pathogenic or likely pathogenic variants in ATP6V1B1 and ATP6V0A4 gene. Children with dRTA have a guarded prognosis and ATP6V1B1 and ATP6V0A4 mutations are the most common implicated genetic defect in Indian children with distal RTA.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common ciliopathies with kidney (nephromegaly, hypertension, renal dysfunction) and liver involvement (congenital hepatic fibrosis, dilated bile ducts). Clinical features also include growth failure and neurocognitive impairment. Plurality of clinical aspects requires multidisciplinary approach to treatment and care of patients. Until recently, diagnosis was based on clinical criteria. Results of genetic testing show the molecular basis of polycystic kidneys disease is heterogeneous, and differential diagnosis is essential. The aim of the article is to discuss the role of genetic testing and its difficulties in diagnostics of ARPKD in children.

Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 ( NUDT15 ) genes have been proposed as key determinants of 6-mercaptopurine (6-MP)-induced myelosuppression in pediatric acute lymphoblastic leukemia (ALL). In the present study, genotypes of TPMT and NUDT15 were investigated in 178 Thai pediatric patients with ALL by the TaqMan SNP genotyping assay and DNA sequencing. The frequency of TPMT*3C was 0.034. Among NUDT15 variants, NUDT15*3 is the most common variant with the allele frequency of 0.073, whereas those of NUDT15*2 , NUDT15*5 , and NUDT15*6 variants were 0.022, 0.011, and 0.039. These data suggest that a high proportion of Thai pediatric ALL patients may be at risk of thiopurine-induced myelosuppression.