ABSTRACT
Ventricular septation is a complex process which involves the major genes of cardiac development, acting on myocardial cells from first and second heart fields, and on mesenchymal cells from endocardial cushions. These genes, coding for transcription factors, interact with each other, and their differential expression conditions the severity of the phenotype. In this chapter, we will describe the formation of the ventricular septum in the normal heart, as well as the molecular mechanisms leading to the four main anatomic types of ventricular septal defects: outlet, inlet, muscular, and central perimembranous, resulting from failure of development of the different parts of the ventricular septum. Experiments on animal models, particularly transgenic mouse lines, have helped us to decipher the molecular determinants of ventricular septation. However, a precise description of the anatomic phenotypes found in these models is mandatory to achieve a better comprehension of the complex mechanisms responsible for the various types of VSDs.
Subject(s)
Disease Models, Animal , Heart Septal Defects, Ventricular , Animals , Humans , Mice , Gene Expression Regulation, Developmental , Heart Septal Defects, Ventricular/genetics , Heart Septal Defects, Ventricular/pathology , Heart Septal Defects, Ventricular/metabolism , Mice, Transgenic , Signal Transduction/genetics , Ventricular Septum/pathology , Ventricular Septum/metabolism , Ventricular Septum/embryologyABSTRACT
The development of a fully functional four-chambered heart is critically dependent on the correct formation of the structures that separate the atrial and ventricular chambers. Perturbation of this process typically results in defects that allow mixing of oxygenated and deoxygenated blood. Atrioventricular septal defects (AVSD) form a class of congenital heart malformations that are characterized by the presence of a primary atrial septal defect (pASD), a common atrioventricular valve (cAVV), and frequently also a ventricular septal defect (VSD). While AVSD were historically considered to result from failure of the endocardial atrioventricular cushions to properly develop and fuse, more recent studies have determined that inhibition of the development of other components of the atrioventricular mesenchymal complex can lead to AVSDs as well. The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has been well-documented in studies using animal models for AVSDs, and in addition, preliminary data suggest that the mesenchymal cap situated on the leading edge of the primary atrial septum may be involved in certain situations as well. In this chapter, we review what is currently known about the molecular mechanisms and animal models that are associated with the pathogenesis of AVSD.
Subject(s)
Disease Models, Animal , Heart Septal Defects , Animals , Heart Septal Defects/genetics , Heart Septal Defects/physiopathology , Heart Septal Defects/pathology , Humans , Signal Transduction , Heart Septal Defects, Atrial/genetics , Heart Septal Defects, Atrial/physiopathology , Heart Septal Defects, Atrial/pathology , Heart Septal Defects, Ventricular/genetics , Heart Septal Defects, Ventricular/physiopathology , Heart Septal Defects, Ventricular/pathologyABSTRACT
Ventricular septal defects (VSD) with outflow tract (OFT) malalignment are a common group of congenital heart diseases with varying severity. The developmental process of these defects is challenging to understand due to the complex nature of cardiac morphogenesis and the difficulties in visualizing the temporal and spatial changes that occur during pathogenesis. However, recent advancements in imaging techniques, such as high-resolution episcopic microscopy, have provided valuable insights into the normal septation of ventricular chambers and OFT alignment. Building upon this knowledge, we have utilized lightsheet microscopy, another innovative imaging method, to further investigate the developmental processes that lead to abnormal formation of the ventricular septum and the malalignment of arterial roots with the ventricular chambers. Our study highlights endocardial cushion hypoplasia and insufficient rotation of the outflow tract as two interrelated central factors contributing to the pathogenesis of these defects. This finding has the potential to enhance our understanding of the etiology of congenital heart diseases and may contribute to the development of improved diagnostic and therapeutic strategies in the future.
Subject(s)
Heart Septal Defects, Ventricular , Animals , Humans , Heart Septal Defects, Ventricular/diagnostic imaging , Heart Septal Defects, Ventricular/pathology , Heart Ventricles/diagnostic imaging , Heart Ventricles/abnormalities , Heart Ventricles/pathologyABSTRACT
Surgical repair of channels between the ventricles is enhanced when the surgeon knows precisely where to place a patch, or baffle, so as to restore septal integrity. The paediatric cardiologist should provide the necessary information. Communication will be enhanced if the same words are used to account for the structures in question. Currently, however, the same term, namely "ventricular septal defect," is used to account for markedly different areas within the heart. Closure of perimembranous defects found in hearts with concordant or discordant ventriculo-arterial connections restores the integrity of the ventricular septum, at the same time separating the systemic and pulmonary blood streams. When both arterial trunks arise from the right ventricle, in contrast, the surgeon when placing a baffle so as to separate the blood streams, does not close the channel most frequently described as the "ventricular septal defect." In this review, we show that the perimembranous lesions as found in hearts with concordant or discordant ventriculo-arterial connections are the right ventricular entrances to the areas subtended beneath the hinges of the leaflets of the aortic or pulmonary valves. When both arterial trunks arise from the right ventricle, and the channel between the ventricles is directly subaortic, then the channel termed the "ventricular septal defect" is the left ventricular entrance to the comparable space subtended beneath the aortic root. We argue that recognition of these fundamental anatomical differences enhances the appreciation of the underlying morphology of the various lesions that reflect transfer, during cardiac development, of the aortic root from the morphologically right to the morphologically left ventricle.
Subject(s)
Heart Septal Defects, Ventricular , Transposition of Great Vessels , Ventricular Septum , Child , Humans , Heart Septal Defects, Ventricular/surgery , Heart Septal Defects, Ventricular/pathology , Heart Ventricles/surgery , Aorta/pathologyABSTRACT
Congenital heart disease (CHD) is an abnormality in the structure or function of the cardio-circulatory system present at birth and the ventricular septal defect (VSD) is the most common CHD in children. This study aimed to determine any differences in the histological structure of primary teeth between both healthy children and those children with ventricular septal defects in Erbil City. Methods enrolled children were divided into two groups. Group I (control) & group II (CHD) aged between 6-10 years old. A total of 44 children were collected, (22 children) in each group. Enamel, dentin, and odontoblast layers were examined histologically. Unpaired t-test used for statistical analysis. Results: The histopathological sections showed a significant difference in enamel, dentin, and odontoblast layer thickness (255.8 ± 41.68- 406.4 ±46.39), (1156 ± 116.0 - 1320 ± 117.4) and (29.74 ± 7.66 -41.38 ± 12.06) respectively, with p values (P < 0.0001) for enamel and dentin layer, and P < 0.0004 for odontoblast layer. A study of the images in the CHD group showed that the tooth tissue lost its integrity and cohesion in some places, and the thickness of the enamel and dentin layer in this group was significantly reduced compared to group I. Tissue loss in enamel, pulp, and dentin cell were observed. Also, connective tissue layers in the pulp were disrupted. Conclusions: CHD can alter the natural structure formation of primary teeth. Histologically, enamel, dentin, and odontoblasts layer thickness reduction are found in primary teeth in children with ventricular septal defects.
Subject(s)
Heart Defects, Congenital , Heart Septal Defects, Ventricular , Infant, Newborn , Humans , Child , Dentin/pathology , Odontoblasts/pathology , Tooth, Deciduous , Heart Septal Defects, Ventricular/pathologyABSTRACT
Decision-making in congenital cardiac care, although sometimes appearing simple, may prove challenging due to lack of data, uncertainty about outcomes, underlying heuristics, and potential biases in how we reach decisions. We report on the decision-making complexities and uncertainty in management of five commonly encountered congenital cardiac problems: indications for and timing of treatment of subaortic stenosis, closure or observation of small ventricular septal defects, management of new-onset aortic regurgitation in ventricular septal defect, management of anomalous aortic origin of a coronary artery in an asymptomatic patient, and indications for operating on a single anomalously draining pulmonary vein. The strategy underpinning each lesion and the indications for and against intervention are outlined. Areas of uncertainty are clearly delineated. Even in the presence of "simple" congenital cardiac lesions, uncertainty exists in decision-making. Awareness and acceptance of uncertainty is first required to facilitate efforts at mitigation. Strategies to circumvent uncertainty in these scenarios include greater availability of evidence-based medicine, larger datasets, standardised clinical assessment and management protocols, and potentially the incorporation of artificial intelligence into the decision-making process.
Subject(s)
Aortic Valve Insufficiency , Heart Defects, Congenital , Heart Septal Defects, Ventricular , Humans , Uncertainty , Artificial Intelligence , Heart Defects, Congenital/therapy , Heart Septal Defects, Ventricular/surgery , Heart Septal Defects, Ventricular/pathologyABSTRACT
Ventricular septal defects (VSDs) are the most common congenital heart defects (CHDs). Studies have documented that ISL1 has a crucial impact on cardiac growth, but the role of variants in the ISL1 gene promoter in patients with VSD has not been explored. In 400 subjects (200 patients with isolated and sporadic VSDs: 200 healthy controls), we investigated the ISL1 gene promoter variant and performed cellular functional experiments by using the dual-luciferase reporter assay to verify the impact on gene expression. In the ISL1 promoter, five variants were found only in patients with VSD by sequencing. Cellular functional experiments demonstrated that three variants decreased the transcriptional activity of the ISL1 promoter (P < 0.05). Further analysis with the online JASPAR database demonstrated that a cluster of putative binding sites for transcription factors may be altered by these variants, possibly resulting in change of ISL1 protein expression and VSD formation. Our study has, for the first time, identified novel variants in the ISL1 gene promoter region in the Han Chinese patients with isolated and sporadic VSD. In addition, the cellular functional experiments, electrophoretic mobility shift assay, and bioinformatic analysis have demonstrated that these variants significantly alter the expression of the ISL1 gene and affect the binding of transcription factors, likely resulting in VSD. Therefore, this study may provide new insights into the role of the gene promoter region for a better understanding of genetic basis of the formation of CHDs and may promote further investigations on mechanism of the formation of CHDs.
Subject(s)
Heart Septal Defects, Ventricular/genetics , LIM-Homeodomain Proteins/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Transcription Factors/genetics , Adolescent , Asian People , Base Sequence , Binding Sites , Case-Control Studies , Child , Child, Preschool , Databases, Genetic , Female , Gene Expression , Genes, Reporter , HEK293 Cells , Heart Septal Defects, Ventricular/ethnology , Heart Septal Defects, Ventricular/metabolism , Heart Septal Defects, Ventricular/pathology , Humans , Infant , LIM-Homeodomain Proteins/metabolism , Luciferases/genetics , Luciferases/metabolism , Male , Protein Binding , Sequence Analysis, DNA , Transcription Factors/metabolism , Ventricular Septum/metabolism , Ventricular Septum/pathologyABSTRACT
Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
Subject(s)
Abnormalities, Multiple/pathology , Adenosine Triphosphatases/genetics , Craniofacial Abnormalities/pathology , DNA Methylation , Epigenesis, Genetic , Growth Disorders/pathology , Heart Septal Defects, Ventricular/pathology , Mutation , Neurodevelopmental Disorders/pathology , Phenotype , Abnormalities, Multiple/genetics , Case-Control Studies , Cohort Studies , Craniofacial Abnormalities/genetics , Female , Genetic Predisposition to Disease , Growth Disorders/genetics , Heart Septal Defects, Ventricular/genetics , Humans , Infant, Newborn , Male , Neurodevelopmental Disorders/geneticsABSTRACT
BACKGROUND: A heterozygous natriuretic peptide receptor 2 (NPR2) gene c.2455C>T mutation was identified as a cause of familial idiopathic short stature (ISS). Only two cases with this mutation were reported previously, and the probands with ISS had no organ system defects. METHODS: Next-generation sequencing (NGS) was performed on an amniotic fluid DNA sample of a fetus with shortened long bones and a small ventricular septal defect detected by an obstetric ultrasound examination. The pathogenic variant of the fetus was confirmed by Sanger sequencing. Sanger sequencing, G-banded, and C-banded karyotyping of the fetus's parents were subsequently performed. RESULTS: A de novo NPR2 gene c.2455C>T, p.(Arg819Cys) mutation was identified in the fetus. No microdeletion or microduplication was identified in the fetus by copy number variation sequencing with a maximum resolution of 400 kb. The two previous miscarriages experienced by the fetus's parents were interpreted as a result of chromosomal aberrations, including a maternal fragile site at 16q22.1 and a rare paternal variant involving in a large G-band-positive and C-band-positive block of paracentric heterochromatin of chromosome 4p. CONCLUSION: This report provides clinical signs of a de novo heterozygous NPR2 gene c.2455C>T mutation in the fetus and shows paternal chromosomal aberrations causing repeated pregnancy loss.
Subject(s)
Chromosome Fragile Sites , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 4/genetics , Heart Septal Defects, Ventricular/genetics , Leg Bones/abnormalities , Receptors, Atrial Natriuretic Factor/genetics , Adult , Amniocentesis , Female , Fetus/abnormalities , Heart Septal Defects, Ventricular/diagnostic imaging , Heart Septal Defects, Ventricular/pathology , Heterochromatin/genetics , Humans , Karyotype , Leg Bones/embryology , Mutation , Pregnancy , Sequence Analysis, DNA , Ultrasonography, PrenatalABSTRACT
BACKGROUND: In human fetuses with Down syndrome, placental pathology, structural anomalies and growth restriction are present. There is currently a significant lack of information regarding the early life span in mouse models of Down syndrome. OBJECTIVE: The objective of this study was to examine embryonic day 18.5 and placental phenotype in the 3 most common mouse models of Down syndrome (Ts65Dn, Dp(16)1/Yey, Ts1Cje). Based on prenatal and placental phenotyping in 3 mouse models of Down syndrome, we hypothesized that one or more of them would have a similar phenotype to human fetuses with trisomy 21, which would make it the most suitable for in utero treatment studies. STUDY DESIGN: Here, C57BL6J/6 female mice were mated to Dp(16)1/Yey and Ts1Cje male mice and Ts65Dn female mice to C57BL/B6Eic3Sn.BLiAF1/J male mice. At embryonic day 18.5, dams were euthanized. Embryos and placentas were examined blindly for weight and size. Embryos were characterized as euploid or trisomic, male or female by polymerase chain reaction. A subset of embryos (34 euploid and 34 trisomic) were examined for malformations. RESULTS: The Ts65Dn mouse model showed the largest differences in fetal growth, brain development, and placental development when comparing euploid and trisomic embryos. For the Dp(16)1/Yey mouse model, genotype did not impact fetal growth, but there were differences in brain and placental development. For the Ts1Cje mouse model, no significant association was found between genotype and fetal growth, brain development, or placental development. Euploid mouse embryos had no congenital anomalies; however, 1 mouse embryo died. Hepatic necrosis was seen in 6 of 12 Dp(16)1/Yey (50%) and 1 of 12 Ts1Cje (8%) mouse embryos; hepatic congestion or inflammation was observed in 3 of 10 Ts65Dn mouse embryos (30%). Renal pelvis dilation was seen in 5 of 12 Dp(16)1/Yey (42%), 5 of 10 Ts65Dn (50%), and 3 of 12 Ts1Cje (25%) mouse embryos. In addition, 1 Ts65Dn mouse embryo and 1 Dp(16)1/Yey mouse embryo had an aortic outflow abnormality. Furthermore, 2 Ts1Cje mouse embryos had ventricular septal defects. Ts65Dn mouse placentas had increased spongiotrophoblast necrosis. CONCLUSION: Fetal and placental growth showed varying trends across strains. Congenital anomalies were primarily seen in trisomic embryos. The presence of liver abnormalities in all 3 mouse models of Down syndrome (10 of 34 cases) is a novel finding. Renal pelvis dilation was also common (13 of 34 cases). Future research will examine human autopsy material to determine if these findings are relevant to infants with Down syndrome. Differences in placental histology were also observed among strains.
Subject(s)
Down Syndrome/genetics , Fetal Development , Placenta/pathology , Placentation , Animals , Brain/embryology , Brain/pathology , Dilatation, Pathologic , Disease Models, Animal , Female , Genotype , Heart Septal Defects, Ventricular/pathology , Inflammation/pathology , Kidney Pelvis/pathology , Liver/pathology , Mice, Inbred C57BL , Necrosis , Organ Size , Phenotype , PregnancyABSTRACT
Ventricular septal defects (VSDs) are the most common congenital heart diseases; however, case reports of preterm infants with VSD are limited. The aim of this study is to share our experience with preterm infants with VSD and to record their short-term outcomes. Between January 2000 and December 2017, 32 preterm infants with VSD were admitted to our neonatal intensive care unit at gestational age < 32 weeks. Of these, 9 were excluded by exclusion criteria. The size and location of the VSD, details of treatment, and neonatal prognosis were retrospectively reviewed from the medical records. Among the 23 preterm infants, the median gestational age was 29.4 weeks (25.0-31.3 weeks) and the median birthweight was 924 g (524-1,526 g). There were 9 infants with VSD < 2 mm and 14 infants with VSD ≥ 2 mm. For the 9 infants with VSD < 2 mm, no medical or surgical treatments for VSDs were undertaken. Of the 14 infants with VSD ≥ 2 mm, 8 (57.1%) underwent medical and surgical treatment. Surgical treatment was performed more frequently in infants with VSD ≥ 2 mm than in those with VSD < 2 mm (P = 0.007). In preterm infants, the presence of VSD ≥ 2 mm increases the risk of surgical interventions and significant patent ductus arteriosus. It is important to encourage treatment for preterm infants with VSD ≥ 2 mm, including surgical interventions, in cooperation with pediatric cardiologists.
Subject(s)
Heart Septal Defects, Ventricular/pathology , Infant, Premature/physiology , Female , Heart Septal Defects, Ventricular/surgery , Humans , Infant, Newborn , MaleABSTRACT
Various congenital heart diseases are associated with malalignment of a part of the ventricular septum. Most commonly, the outlet septum is malaligned toward the right or left ventricle. Less commonly, the whole or a major part of the ventricular septum is malaligned in relation to the atrial septal plane. Although the pathological conditions associated with ventricular septal malalignment have been well recognized, the descriptions are often confusing and sometimes incorrect. In this pictorial essay, we introduce our systematic approach to the assessment of malalignment type ventricular septal defects with typical case examples. The systematic approach comprises description of the essential features of malalignment, including the following: (1) the malaligned part of the ventricular septum, (2) the reference structure, (3) the mechanism of malalignment, (4) the direction of malalignment, and (5) the severity of malalignment.
Subject(s)
Heart Septal Defects, Ventricular/pathology , Heart Septal Defects, Ventricular/surgery , Heart Septal Defects, Ventricular/classification , HumansABSTRACT
LACHT syndrome, or Mardini-Nyhan association, is an ultra-rare disorder, diagnosed solely by the clinical characteristics of lung agenesis, complex cardiac defects, and thumb anomalies. Only 12 patients have been reported worldwide, and here, we report a new clinical diagnosis of LACHT syndrome. Our patient was a male full-term newborn with left lung agenesis, congenital heart defects including ventricular septal defect, right-sided aortic arch, with aberrant left subclavian artery and Kommerell diverticulum, as well as left preaxial polydactyly and hemivertebra. Our patient appears to be the second LACHT syndrome case to also suffer from tracheal stenosis, which has only been reported once before in conjunction with this syndrome. In light of this, tracheal stenosis may be a phenotype for LACHT syndrome.
Subject(s)
Abnormalities, Multiple/diagnosis , Cardiovascular Abnormalities/diagnosis , Lung Diseases/diagnosis , Lung/abnormalities , Polydactyly/genetics , Subclavian Artery/abnormalities , Thumb/abnormalities , Tracheal Stenosis/diagnosis , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Adult , Aorta, Thoracic/diagnostic imaging , Aorta, Thoracic/pathology , Cardiovascular Abnormalities/diagnostic imaging , Cardiovascular Abnormalities/pathology , Female , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/diagnostic imaging , Heart Defects, Congenital/pathology , Heart Septal Defects, Ventricular/diagnosis , Heart Septal Defects, Ventricular/diagnostic imaging , Heart Septal Defects, Ventricular/pathology , Humans , Infant, Newborn , Lung/diagnostic imaging , Lung/pathology , Lung Diseases/diagnostic imaging , Lung Diseases/pathology , Male , Polydactyly/diagnostic imaging , Polydactyly/pathology , Subclavian Artery/diagnostic imaging , Subclavian Artery/pathology , Thailand/epidemiology , Thumb/diagnostic imaging , Thumb/pathology , Tracheal Stenosis/diagnostic imaging , Tracheal Stenosis/pathologyABSTRACT
BACKGROUND: Bicuspid aortic valve is the most common congenital valvular heart defect in the general population. BAV is associated with significant morbidity due to valve failure, formation of thoracic aortic aneurysm, and increased risk of infective endocarditis and aortic dissection. Loss of function mutations in NOTCH1 (OMIM 190198) has previously been associated with congenital heart disease involving the aortic valve, left ventricle outflow tract, and mitral valve that segregates in affected pedigrees as an autosomal dominant trait with variable expressivity. METHODS: We performed whole-exome sequencing in four members of a three-generational family (three affected and one unaffected subject) with clinical phenotypes including aortic valve stenosis, thoracic aortic aneurysm, and ventricular septal defect. RESULTS: We identified 16 potentially damaging genetic variants (one stop variant, one splice variant, and 14 missense variants) cosegregating with the phenotype. Of these variants, the nonsense mutation (p.Tyr291*) in NOTCH1 was the most deleterious variant identified and the most likely variant causing the disease. CONCLUSION: Inactivating NOTCH1 mutations are a rare cause of familial heart disease involving predominantly left ventricular outflow tract lesions and characterized by the heterogeneity of clinical phenotype.
Subject(s)
Aortic Aneurysm, Thoracic/genetics , Aortic Valve Stenosis/genetics , Bicuspid Aortic Valve Disease/genetics , Heart Septal Defects, Ventricular/genetics , Loss of Function Mutation , Receptor, Notch1/genetics , Adult , Aged , Aortic Aneurysm, Thoracic/pathology , Aortic Valve Stenosis/pathology , Bicuspid Aortic Valve Disease/pathology , Codon, Nonsense , Female , Heart Septal Defects, Ventricular/pathology , Humans , Male , Middle Aged , Pedigree , PhenotypeABSTRACT
BACKGROUND: Congenital disorder of glycosylation (CDG) type I is a group of rare disorders caused by recessive mutations in up to 25 genes that impair the N-glycan precursor formation and its transfer to proteins resulting in hypoglycosylation of multiple proteins. Congenital disorder of glycosylation causes multisystem defects usually with psychomotor delay that is diagnosed in the infancy. We aim to supply further evidences supporting that CDG may be underestimated. METHODS: Antithrombin and factor XI were studied by chromogenic and coagulometric methods. Hypoglycosylation of plasma proteins was evaluated by western blot, HPLC, Q-TOF, and RP-LC-MRM-MS. Genetic analysis included whole exome, Sanger sequencing, and PCR-allele specific assay. RESULTS: We here present an intriguing patient with an exceptional phenotype: 25-year-old women with a ventricular septal defect and severe idiopathic scoliosis but no facial dysmorphism, who dances as a professional, and has a University degree. Congenital disorder of glycosylation diagnosis started through the identification of antithrombin deficiency without SERPINC1 defect and the detection of hypoglycosylated forms. Increased levels of hypoglycosylated forms of F XI (also with significant deficiency) and transferrin were also detected. Whole exome analysis showed a novel homozygous ALG12 variant c.77T>A, p.(Val26Asp) supporting an ALG12-CDG diagnosis. It also showed three new variants in KMT2D, and a mild, known ALG6 variant. CONCLUSIONS: This novel ALG12-CDG patient (the 13th reported) underlines the heterogeneity of this CDG and broadens its phenotypical spectrum, supports that these disorders are underestimated, and suggests that combination of global hypoglycosylation with specific gene defects might determine the clinical manifestations of CDG patients.
Subject(s)
Congenital Disorders of Glycosylation/genetics , Heart Septal Defects, Ventricular/genetics , Mannosyltransferases/genetics , Phenotype , Scoliosis/genetics , Academic Success , Adult , Congenital Disorders of Glycosylation/pathology , DNA-Binding Proteins/genetics , Female , Glucosyltransferases/genetics , Heart Septal Defects, Ventricular/pathology , Humans , Membrane Proteins/genetics , Mutation , Neoplasm Proteins/genetics , Scoliosis/pathologySubject(s)
Aortic Rupture/diagnosis , Heart Defects, Congenital/diagnosis , Heart Septal Defects, Ventricular/diagnosis , Sinus of Valsalva/pathology , Adult , Cardiovascular Abnormalities/complications , Diagnosis, Differential , Dyspnea/diagnosis , Dyspnea/etiology , Echocardiography/methods , Electrocardiography/methods , Heart Septal Defects, Ventricular/complications , Heart Septal Defects, Ventricular/pathology , Heart Septal Defects, Ventricular/surgery , Humans , Hypertrophy, Left Ventricular/diagnosis , Male , Treatment Outcome , Ventricular Outflow Obstruction/diagnostic imaging , Ventricular Outflow Obstruction/surgerySubject(s)
Atrial Appendage/abnormalities , Atrial Appendage/pathology , Heart Defects, Congenital/pathology , Heart Septal Defects, Atrial/diagnostic imaging , Heart Septal Defects, Ventricular/pathology , Respiratory Distress Syndrome, Newborn/etiology , Atrial Appendage/diagnostic imaging , Biopsy , Echocardiography, Three-Dimensional , Fatal Outcome , Heart Defects, Congenital/complications , Heart Defects, Congenital/diagnostic imaging , Humans , Infant , MaleABSTRACT
Myeloid ecotropic insertion site 2 (MEIS2) gene, encoding a homeodomain-containing transcription factor, has been recently related to syndromic intellectual disability with cleft palate and cardiac defects. Here, we present a male patient, aged 10, with cardiac defects, intellectual disability, facial dysmorphisms and gastroesophageal reflux. Whole exome sequencing revealed a novel de novo nonsense mutation in the MEIS2 gene. This patient represents another reported case with a de novo MEIS2 point mutation and helps to characterize a distinct facial phenotype consisting in low anterior hairline, thin eyebrows, anteverted nares, hypoplastic alae nasi, and M-shape upper lip. Furthermore, these data confirm the role of this gene in cardiac, nervous system development and gastrointestinal function.