ABSTRACT
Congenital anomalies (CA) affect 3-5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients.
Subject(s)
Abnormalities, Multiple , Heart Defects, Congenital , Abnormalities, Multiple/genetics , Algorithms , Genetic Testing , Heart Defects, Congenital/genetics , Histone Acetyltransferases , Humans , KaryotypingABSTRACT
INTRODUCCIÓN: Las cardiopatías congénitas (CC) son causadas por el desarrollo anómalo del corazón durante el período embriofetal. Abarcan un amplio espectro de anomalías estructurales de las cavidades cardíacas o de los grandes vasos, con una prevalencia mundial de 6 a 9 por 1000 nacimientos. En Argentina constituyen un tercio de las anomalías congénitas (AC) al nacimiento. Si bien su etiología es heterogénea, se ha observado recurrencia familiar acorde con la influencia de factores genéticos. El objetivo del estudio fue evaluar la presencia de anomalías cromosómicas, desbalances genómicos o variantes de secuencias en una muestra de niños afectados con CC en Argentina. MÉTODOS: Se incluyó a 289 pacientes con CC de hasta 16 años. Se realizó un cariotipo para pacientes con otras AC y análisis por amplificación múltiple de sondas dependiente de ligación (MLPA) de regiones genómicas asociadas a CC para aquellos con CC conotroncales. En muestras seleccionadas, se analizaron desbalances genómicos por microarreglos de ADN (array-CGH) o variantes de secuencia en el gen NKX2-5. RESULTADOS: Hubo 9 pacientes que presentaron anomalías cromosómicas, 21 desbalances por MLPA y 8 por array-CGH. No se hallaron variantes patogénicas en NKX2-5 en los casos estudiados. DISCUSIÓN: Se halló la causa de la afección en el 13% de los casos analizados. El estudio de pacientes con CC aisladas o asociadas a otras AC no había sido abordado previamente en Argentina mediante este algoritmo
Subject(s)
Chromosome Aberrations , Genetics, Medical , Heart DiseasesSubject(s)
ATP-Dependent Proteases/genetics , ATPases Associated with Diverse Cellular Activities/genetics , Intellectual Disability/diagnostic imaging , Intellectual Disability/genetics , Muscle Spasticity/diagnostic imaging , Muscle Spasticity/genetics , Optic Atrophy/diagnostic imaging , Optic Atrophy/genetics , Spinocerebellar Ataxias/diagnostic imaging , Spinocerebellar Ataxias/genetics , Adult , Humans , Magnetic Resonance Imaging , Male , Metalloendopeptidases/genetics , Pedigree , Siblings , Exome Sequencing , Young AdultABSTRACT
Chromosomal trisomies are the most frequent major chromosomal anomalies in humans and can be present in a mosaic or a non-mosaic constitution. We report the first case of a newborn girl presenting with multiple congenital anomalies and a double mosaic trisomy involving chromosome 14 and the X chromosome detected by array CGH. Karyotype analysis revealed a double mosaic with 2 independent abnormal cell lines and the absence of 46,XX and 48,XXX,+14 cell lineages. The patient showed most of the clinical characteristics of mosaic trisomy 14. Analysis of autosomal DNA markers in the proband's blood sample did not support the presence of chimerism. Further analysis of chromosome X DNA markers suggests that the extra X chromosome most probably arose as a consequence of nondisjunction in meiosis II in the maternal lineage.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, X , Mosaicism , Sex Chromosome Disorders of Sex Development/genetics , Trisomy/genetics , Chromosomes, Human, Pair 14 , Chromosomes, Human, X/genetics , Female , Humans , Infant, Newborn , Sex Chromosome AberrationsABSTRACT
Congenital conotruncal heart defects (CCHD) are a subset of serious congenital heart defects (CHD) of the cardiac outflow tracts or great arteries. Its frequency is estimated in 1/1000 live births, accounting for approximately 10â»30% of all CHD cases. Chromosomal abnormalities and copy number variants (CNVs) contribute to the disease risk in patients with syndromic and/or non-syndromic forms. Although largely studied in several populations, their frequencies are barely reported for Latin American countries. The aim of this study was to analyze chromosomal abnormalities, 22q11 deletions, and other genomic imbalances in a group of Argentinean patients with CCHD of unknown etiology. A cohort of 219 patients with isolated CCHD or associated with other major anomalies were referred from different provinces of Argentina. Cytogenetic studies, Multiplex-Ligation-Probe-Amplification (MLPA) and fluorescent in situ hybridization (FISH) analysis were performed. No cytogenetic abnormalities were found. 22q11 deletion was found in 23.5% of the patients from our cohort, 66% only had CHD with no other major anomalies. None of the patients with transposition of the great vessels (TGV) carried the 22q11 deletion. Other 4 clinically relevant CNVs were also observed: a distal low copy repeat (LCR)D-E 22q11 duplication, and 17p13.3, 4q35 and TBX1 deletions. In summary, 25.8% of CCHD patients presented imbalances associated with the disease.
ABSTRACT
INTRODUCCIÓN El virus Zika (ZIKV) es un flavivirus. La transmisión vertical puede provocar microcefalia y/u otras anomalías congénitas. En Argentina el vector Aedes Aegypti tiene amplia distribución y desde 2016 hay brotes de ZIKV. OBNETIVOS Conocer la situación epidemiológica de la microcefalia y/o anomalías cerebrales seleccionadas en la red de maternidades de la Red Nacional de Anomalías Congénitas (RENAC). MÉTODOS Se incluyeron recién nacidos de la RENAC desde 4/ 2016 a 3/2017. Caso; recién nacidos con perímetro cefálico menor al percentilo 3 según edad gestacional y sexo. Se analizó sangre y orina de madre y recién nacido. Para ZIKV se realizó PCR, ELISA IgM y neutralización por reducción de placas (PRNT). Se evaluó infección por toxoplasmosis, rubéola, herpes simple, lúes, citomegalovirus (CMV). RESULTADOS Se detectaron 104 casos, prevalencia 6,9 por 10.000 (IC95%;5,7-8,4), resultando un incremento significativo al comparar con el año 2015, RP 1,7 (IC 95%;1,2-2,3). Las jurisdicciones con transmisión sostenida de dengue no mostraron diferencias significativas con aquellas sin transmisión, RP 1,06 (IC 95% 0,6-2,0). Se detectó una causa conocida específica 25%, microcefalia por una malformación cerebral específica 9,6% y sin causa definida 65,4%. En 4 casos se detectó serología positiva para ZIKV, 2 fueron autóctonos y 2 importados. Los 4 casos presentaron microcefalia con desproporción craneofacial y en un caso artrogriposis. Además se detectaron; 4 casos de infección por CMV, 3 por toxoplasmosis, 2 por herpes simple y 1 lúes congénita. No hubo casos de rubéola. DISCUSIÓN La prevalencia fue significativamente mayor a la detectada en la RENAC en el período previo. Esta situación podría estar indicando un aumento real en la prevalencia o bien puede explicarse por el efecto del conocimiento. El sistema permitió detectar cuatro casos con síndrome de ZIKV congénito, en un país que ha tenido brotes aislados de esta enfermedad
Subject(s)
Congenital Abnormalities , Zika Virus , Zika Virus Infection , MicrocephalyABSTRACT
Complete absence of the fetal head in singleton pregnancies is a very rare defect; to our knowledge there are only 7 reported cases. Decapitation by amniotic bands has been considered as the most probable cause. However, in none of the described cases except one were amniotic bands, constriction rings, or other related findings observed, raising the possibility that mechanisms other than amputation by amniotic bands are involved. We present a further case of acephaly and discuss the role of amniotic bands and alternative mechanisms of decapitation and a possible sequence of events leading to acephaly.
