Other genomic disorders and congenital heart disease

Congenital heart disease (CHD) is the common birth defect worldwide. Despite its recognized burden on public health, the etiology in the vast majority of individuals remains unknown. Chromosomal abnormality plays an important role, frequently observed as large cytogenetically visible rearrangement or small submicroscopic structural variation in the genome. Several genomic disorders are now recognized that are increasingly responsible for CHD with variable penetrance. Single gene disorders, epigenetic alterations, and environmental etiologies are also significant contributors. Our understanding of the genetic basis of CHD has increased exponentially with the escalating use of next generation sequencing to identify ever so small submicroscopic genomic imbalances at the level of coding exons in CHD. This review focuses on genomic disorders other than 22q11.2 deletion, that are major players in the etiology of human cardiac malformations.     

Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes

CHARGE syndrome is characterized by a pattern of congenital anomalies (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital abnormalities, and Ear abnormalities). De novo mutations of chromodomain helicase DNA binding protein 7 (CHD7) are the primary cause of CHARGE syndrome. The clinical phenotype is highly variable including a wide spectrum of congenital heart defects. Here, we review the range of congenital heart defects and the molecular effects of CHD7 on cardiovascular development that lead to an over‐representation of atrioventricular septal, conotruncal, and aortic arch defects in CHARGE syndrome. Further, we review the overlap of cardiovascular and noncardiovascular comorbidities present in CHARGE and their impact on the peri‐operative morbidity and mortality in individuals with CHARGE syndrome.     

Endomyometriosis arising in the uterosacral ligament: a case report including a literature review and immunohistochemical analysis

We report a case of endomyometriosis arising in the left uterosacral ligament of a 29-year-old woman. The central cavity of the uterine-like mass was lined by pseudo-stratified columnar epithelium and endometrial stroma. The wall of the cyst consisted of bundles of smooth muscle cells. Immunohistochemical analysis demonstrated both alpha-estrogen receptor and progesterone receptor immunoreactivities in the epithelial, stromal and smooth muscle cells. A relatively high proliferating activity was also demonstrated in these cells by Ki-67 immunostaining. These findings suggest that the mass was hormone dependent and had a relatively rapid evolution.     

New multiple congenital anomalies: Mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement

Five unrelated patients (a male and 4 females) were affected with a previously undefined multiple congenital anomalies/mental retardation syndrome which has been designated the facio-cutaneous-skeletal (FCS) syndrome and which includes mental retardation with specific sociable, humorous behavior, characteristic facial appearance, excessive generalized skin, postnatal growth failure, and skeletal involvement. Consanguinity was noted in 2 patients, thus autosomal recessive inheritance is suggested. © 1992 Wiley-Liss, Inc.     

Anti-P30 IgA antibodies as prenatal markers of congenital toxoplasma infection

This study extends a previous study and confirms that the detection of anti-P30 IgA antibodies is very helpful in the diagnosis of acute acquired or congenital toxoplasmosis. Moreover, we demonstrate that an anti-P30 IgA response can be mounted in the fetuses infected by Toxoplasma gondii during their intra-uterine life as early as week 23 of gestation. A double-sandwich ELISA described in our previous work was used to detect anti-P30 IgA antibodies in 1378 human serum samples collected from 551 patients, including 162 fetuses whose mothers had been infected by T. gondii during pregnancy, 46 congenitally infected and 90 uninfected newborns and 253 women suspected of having been infected during pregnancy, including the mothers of fetuses and newborns previously described. Anti-P30 IgA antibodies were detected in all cases of acute toxoplasmosis but in no case of chronic toxoplasmosis: in the majority of cases, the IgA antibody titre fell below cut-off in 3-9 months. Among the 46 congenitally infected newborns, anti-P30 IgA antibodies were detected in sera of 41 infected newborns (38 at birth, two in the first months of life, one in the seventh month of life), while anti-P30 IgM antibodies were detected in only 30 cases at birth and in one case during the first month of life. Among 162 fetuses, anti-P30 IgA response was observed in five infected fetuses, but was not detected in either 152 uninfected fetuses or in five fetuses considered as infected. The absence or presence of anti-P30 IgA antibodies in the fetus is discussed in relation to the date of maternal infection and collection of the fetal blood. It clearly appears from our study that the combined testing of both IgM and IgA in the fetus and the newborn is essential for a more efficient diagnosis of infection.     

Autoantibody response to the Ro/La particle may predict outcome in neonatal lupus erythematosus.

This study was undertaken to determine the role of antibodies against both recombinant Ro (r-Ro) and La (r-La) proteins and polypeptides derived from the recombinant La protein in predicting fetal and neonatal outcome in children at risk to develop neonatal lupus erythematosus (NLE). All sera were obtained in the perinatal period and quantitative ELISA assays were used. We collected 41 maternal sera within 2 months of delivery of a child with NLE (21 with congenital heart disease block (CHB) and 20 with dermatologic NLE) and 19 sera from anti-Ro and/or anti-La antibody-positive mothers with systemic lupus erythematosus (SLE) who delivered a child without NLE. All sera were tested for anti-r-La and anti-r-Ro antibodies by ELISA, and most sera were tested for antibodies directed against La polypeptides by immunoblot. We found significantly higher anti-r-La antibody levels in the sera from mothers of children with NLE compared with sera from mothers of unaffected children (0.67 +/- 0.43 versus 0.14 +/- 0.30; P < 0.0001). There was a statistically significant difference in the mean anti-r-La levels between the sera of mothers of children with CHB compared with dermatologic NLE (0.51 +/- 0.45 versus 0.83 +/- 0.37 respectively; P = 0.0091). When we examined antibodies directed against the recombinant 52-kD Ro protein, there was a statistically significant elevation of titres in the sera of mothers of NLE children (0.77 +/- 0.35) compared with non-NLE mothers (0.29 +/- 0.39; P < 0.0001). There was no difference in the r-Ro levels between mothers of children with dermatologic NLE compared with CHB (0.82 +/- 0.37 versus 0.71 +/- 0.74; P = 0.32). When we examined polypeptides derived from the recombinant La protein, the mean number of polypeptides recognized by sera from mothers of children with NLE was significantly higher than the mean number of polypeptides recognized by sera from mothers of unaffected children (5.1 +/- 0.54 versus 2.3 +/- 0.54 respectively; P < 0.001). More importantly, when we examined the individual polypeptides, we found that only sera from mothers of children with NLE and not from mothers of unaffected children recognized a polypeptide designated DD (30% versus 0%, respectively). These studies indicate that the autoantibody response to the Ro/La particle can differentiate sera from mothers of children with NLE and sera from mothers of unaffected children. Furthermore, there was a difference in the anti-La autoantibody response between mothers of children with CHB and dermatologic NLE.(ABSTRACT TRUNCATED AT 400 WORDS)     

GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.     

先天性软骨发育不全成纤维细胞生长因子受体3基因1138位核苷酸点突变的检测

目的 验证成纤维细胞生长因子受体3(fibroblast growth factor receptor 3，FGFR3)跨膜区1138位核苷酸为先天性软骨发育不全突变热点及用变性梯度电泳方法筛查的效果。方法 对17例临床诊断为先天性软骨发育不全患者进行基因组DNA聚合酶链反应－限制性酶切片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)分析，并用变性梯度凝胶电泳（denaturing gradient gel electrophoresis,DGGE)进行其它突变位点的筛查。结果 17例患者中14例RFLP检测显示能被Sfc I酶切，提示存在1138位核苷酸G→A的转换，且均为杂合子。17例用Msp I酶切均阴性，提示无G→C的颠换。DGGE方法的筛查中，酶切阳性的14例标本均显示存在杂合型突变。3例PCR－RFLP检测阴性的标本未显示突变位点，提示在该扩增区域确实不存在突变位点。结论 FGFR3跨膜区1138核苷酸G→A的突变是软骨发育不全的主要发病机理，DGGE可作为筛查某一区域基因突变的敏感而可靠的检测手段，尤其是对杂合子的检测。     

A deletion–insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation‐Ia

Congenital disorders of glycosylation (CDG) are a group of metabolic disorders with multisystemic involvement characterized by abnormalities in the synthesis of N‐linked oligosaccharides. The most common form, CDG‐Ia, resulting from mutations in the gene encoding the enzyme phosphomannomutase (PMM2), manifests with severe abnormalities in psychomotor development, dysmorphic features and visceral involvement. While this disorder is panethnic, we present the first cases of CDG‐Ia identified in an African American family with two affected sisters. The proband had failure to thrive in infancy, hypotonia, ataxia, cerebellar hypoplasia and developmental delay. On examination, she also exhibited strabismus, inverted nipples and an atypical perineal fat distribution, all features characteristic of CDG‐Ia. Direct sequencing demonstrated that the patient had a unique genotype, T237M/c.565‐571 delAGAGAT insGTGGATTTCC. The novel deletion–insertion mutation, which was confirmed by subcloning and sequencing of each allele, introduces a stop codon 11 amino acids downstream from the site of the deletion. The presence of this deletion–insertion mutation at cDNA position 565 suggests that this site in the PMM2 gene may be a hotspot for chromosomal breakage. Published 2002 Wiley‐Liss, Inc.