PAX2 mutations in fetal renal hypodysplasia Martinovic-Bouriel, Jelena; Benachi, Alexandra; Bonnière, Maryse ...
American journal of medical genetics. Part A,
April 2010, Letnik:
152A, Številka:
4
Journal Article
Recenzirano
Papillorenal syndrome also known as renal-coloboma syndrome (OMIM 120330) is an autosomal dominant condition comprising optic nerve anomaly and renal oligomeganephronic hypoplasia. This reduced ...number of nephron generations with compensatory glomerular hypertrophy leads towards chronic insufficiency with renal failure. We report on two fetuses with PAX2 mutations presenting at 24 and 18 weeks' gestation, respectively, born into two different sibships. In our first patient, termination of pregnancy was elected for anhydramnios and suspicion of renal agenesis in the healthy couple with an unremarkable previous clinical history. This fetus had bilateral asymmetric kidney anomalies including a small multicystic left kidney, and an extremely hypoplastic right kidney. Histology showed dysplastic lesions in the left kidney, contrasting with rather normal organization in the hypoplastic right kidney. Ocular examination disclosed bilateral optic nerve coloboma. The association of these anomalies, highly suggestive of the papillorenal syndrome, led us to perform the molecular study of the PAX2 gene. Direct sequencing of the PAX2 coding sequence identified a de novo single G deletion of nucleotide 935 in exon 3 of the PAX2 resulting in a frameshift mutation (c.392delG, p.Ser131Thrfs*28). In the second family, the presence of a maternally inherited PAX2 mutation led to a decision for termination of pregnancy. The 18-week gestation fetus presented the papillorenal syndrome including hypoplastic kidneys and optic nerve coloboma. In order to address the PAX2 involvement in isolated renal "disease," 18 fetuses fulfilling criteria were screened: 10/18 had uni- or bilateral agenesis, 6/18 had bilateral multicystic dysplasia with enlarged kidneys, and 2/18 presented bilateral severe hypodysplasia confirmed on fetopathological examination. To the best of our knowledge, our first patient represents an unreported fetal diagnosis of papillorenal syndrome, and another example of the impact of oriented fetopathological examination in genetic counseling of the parents.
Summary Background Congenital left coronary artery abnormalities such as ostial stenosis or atresia are extremely rare. Diagnosis in the neonate has not been reported. Aims To describe five neonates ...with left coronary artery orifice abnormalities and discuss pathophysiology, diagnosis and treatment options, with a focus on the importance of autopsy in unexpected neonatal death. Methods Retrospective assessment of medical files of neonates with left coronary abnormalities seen during a 12-year period (2000–2012). Results Three neonates with anatomical ( n = 2) and functional ( n = 1) left coronary stenosis and two neonates with ostial atresia were identified. The three infants with coronary stenosis died within minutes to days after birth because of cardiac failure refractory to intensive care treatment; at autopsy, left coronary ostial stenosis ( n = 2) and high take-off with acute angle origin and tangential vertical course ( n = 1) were diagnosed. The fourth neonate was in cardiac failure due to critical aortic stenosis; left coronary ostial atresia was diagnosed during an emergency catheter procedure and the infant died after aortic valve dilatation. The fifth infant had a cardiac arrest on the third day of life; she was diagnosed with left coronary ostial atresia by coronary angiography and died during attempted revascularization surgery at 2 weeks of life. Conclusion Congenital coronary ostial abnormalities can lead to severe heart failure and unexpected neonatal death. Systematic examination of the coronary arteries should be part of any neonatal autopsy. Coronary angiography remains the diagnostic method of choice despite advances in non-invasive imaging. Revascularization surgery seems indicated in symptomatic children based on small patient series.
Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of ...cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co‐dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.
Fetal cardiomyopathies are rare and could led to in utero fetal death or termination of pregnancy. Morphological analysis of 16 cases allowed to described their characteristics. Genetic analysis on a panel of cardiomyopathy genes has attested of a genetic origin of these cases and also highlighted a particular pattern (high rate of de novo mutation, compound heterozygous and co‐dominance) participating to the explanation of a severe cardiomyopathy. This work confirmed the interest of genetic testing of fetal cardiomyopathies to improve genetic counselling in the families.
Rare lethal disease gene identification remains a challenging issue, but it is amenable to new techniques in high-throughput sequencing (HTS). Cerebral proliferative glomeruloid vasculopathy (PGV), ...or Fowler syndrome, is a severe autosomal recessive disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels leading to hydranencephaly. In three multiplex consanguineous families, genome-wide SNP analysis identified a locus of 14 Mb on chromosome 14. In addition, 280 consecutive SNPs were identical in two Turkish families unknown to be related, suggesting a founder mutation reducing the interval to 4.1 Mb. To identify the causative gene, we then specifically enriched for this region with sequence capture and performed HTS in a proband of seven families. Due to technical constraints related to the disease, the average coverage was only 7x. Nonetheless, iterative bioinformatic analyses of the sequence data identified mutations and a large deletion in the FLVCR2 gene, encoding a 12 transmembrane domain-containing putative transporter. A striking absence of alpha-smooth muscle actin immunostaining in abnormal vessels in fetal PGV brains, suggests a deficit in pericytes, cells essential for capillary stabilization and remodeling during brain angiogenesis. This is the first lethal disease-causing gene to be identified by comprehensive HTS of an entire linkage interval. Hum Mutat 31:1-8, 2010.
Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare autosomal recessive neurodegenerative disease belonging to the family of DNA repair disorders, characterized by microcephaly, congenital ...cataracts, facial dysmorphism and arthrogryposis. Here, we describe the detailed morphological and microscopic phenotype of three fetuses from two families harboring ERCC5/XPG likely pathogenic variants, and review the five previously reported fetal cases. In addition to the classical features of COFS, the fetuses display thymus hyperplasia, splenomegaly and increased hematopoiesis. Microencephaly is present in the three fetuses with delayed development of the gyri, but normal microscopic anatomy at the supratentorial level. Microscopic anomalies reminiscent of pontocerebellar hypoplasia are present at the infratentorial level. In conclusion, COFS syndrome should be considered in fetuses when intrauterine growth retardation is associated with microcephaly, arthrogryposis and ocular anomalies. Further studies are needed to better understand XPG functions during human development.
Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary ...conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes.
Thrombocytopenia‐absent radius (TAR) syndrome is characterized by radial defect and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene (1q21.1) with the association of a null ...allele and a hypomorphic noncoding variant. RBM8A encodes Y14, a core protein of the exon junction complex involved in messenger RNA maturation. To date, only two hypomorphic variants have been identified. We report on a cohort of 26 patients affected with TAR syndrome and carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A were identified in the remaining patients. We developed experimental models enabling their functional characterization in vitro. Two variants, located respectively in the 5′‐untranslated region (5′‐UTR) and 3′‐UTR regions, are responsible for a diminished expression whereas two intronic variants alter splicing. Our results bring new insights into the molecular knowledge of TAR syndrome and enabled us to propose genetic counseling for patients' families.
Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth syndrome. Clinical features are highly variable, including occasional posterior fossa malformations but no femoral shortening.
We ...report two fetuses with BWS associated with short femurs and corpus callosum hypoplasia. Case 2 was growth restricted. BWS was confirmed by molecular studies showing a loss of methylation at ICR2 at 11p15 chromosomic region in case 1 and a gain of methylation at ICR1 and a loss of methylation at ICR2 locus in case 2.
Although the phenotype and the genotype of BWS is now well-known, the presence of corpus callosum abnormalities and short femurs expand the phenotypic spectrum of the disorder.
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