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.
Abstract only
In 2007, Keays et al identified in an ENU‐induced mutant mouse, a mutation in
Tuba1a,
a gene coding for alpha 1 tubulin protein, associated with behavioral disorders and a disturbance ...of the cortical cytoarchitectony. Subsequently, mutations of
TUBA1A
were found in children with mental retardation and lissencephaly with abnormalities of the corpus callosum and cerebellum, on MRI. Recently, mutations of
TUBA1A
were found in 4 fetuses, with a prenatal diagnosis of cerebral dysgenesis leading to a medical termination of pregnancy according to French laws.
These fetuses, not mutated for
LIS1
,
DCX
and
ARX,
were studied at 23, 25, 26 and 35 gestational weeks respectively. The neuropathological study demonstrated a phenotype including abnormalities affecting constantly the neocortex, hippocampus, corpus callosum, cerebellum and brainstem, and inconstantly, basal ganglia, olfactory bulbs and subventricular germinal zones. This phenotype was different from that of
LIS1
,
DCX
,
ARX
lissencephalies, and in agreement with the pattern of expression of
TubA1A
studied in the mouse embryo. Compared with children mutated for
TUBA1A
, fetal cases are located at the most severe end of the spectrum, suggesting that prenatally diagnosed cases are probably the most severe forms of
TUBA1A
lissencephaly.
Improvements in the diagnosis of congenital malformations explain the increasing early termination of pregnancies. Before 13 weeks of gestation, an accurate in vivo anatomic diagnosis cannot ...currently be made in all fetuses with current imaging instrumentation. Anatomopathologic examinations remain the gold standard to make accurate diagnoses, although they reach limits between 9 and 13 weeks of gestation. We present the first results of a methodology that can be applied routinely, using standard histologic section, thus enabling the reconstruction, visual estimate, and quantitative analysis of 13-week human embryonic cardiac structures. The cardiac blocks were fixed, embedded in paraffin, and entirely sliced by a microtome. One of 10 slices was topographically colored and digitized on an optical microscope. Cardiac volume was recovered by semiautomatic realignment of the sections. Another semiautomatic procedure allowed extracting and labeling of cardiac structures from the volume. Structures were studied with display tools, which disclosed the internal and external cardiac components and enabled determination of size, thickness, and precise positioning of ventricles, atria, and large vessels. This pilot study confirmed that a new 3-dimensional reconstruction and visualization method enables accurate diagnoses, including in embryos younger than 13 weeks. Its implementation at earlier stages of embryogenesis will provide a clearer view of cardiac development.
Congenital mesoblastic nephroma (CMN) is a rare renal tumor of early infancy with a favorable outcome after complete surgical removal. CMN consists of a heterogeneous group of spindle cell tumors ...subdivided into “classical”, “cellular or atypical” and “mixed” forms based on histologic features. We describe a new case of cellular CMNdiagnosed by antenatal ultrasonography with complete remission five years after nephrectomy. Cytogenetic study evidenced a trisomy 11, and real time RT-PCR, but not conventional karyotype, allowed for the detection of the Tel-ETV6/TrkC-NTRK3 fusion transcript as a consequence of a cryptic t(12–15)(p13;q25). As in congenital fibrosarcoma (CFS), two Tel-ETV6/ TrkC-NTRK3 fusion transcripts different by a 42 bp insert in the TrkC kinase domain were expressed. Our observations outline the close links between cellular CMNand CFS. Both tumors have the clinical presentation and histologic features as well as identical cytogenetic and molecular markers in common. Therefore, they are likely to represent the same neoplasm, but occurring at different locations.
BACKGROUNDHereditary lymphedema 1 is a rare congenital condition, characterized by the development of chronic swelling in body parts. It is highly variable in expression and age of onset with ...different presentations: from feet edema to hydrops fetalis. This affection is genetically heterogeneous with autosomal dominant inheritance and incomplete penetrance due to a mutation in the FLT4 gene in most cases. CASESIn our study, we report on two fetuses harboring congenital lymphedema with FLT4 variation and review the prenatal confirmed ones of the literatures. Our cases were selected within fetuses explored by exome sequencing in a diagnosis setting. Prenatal ultrasonography showed hydrops fetalis in one case and an increased nuchal translucency with hydrothorax in the other. Comparative genomic hybridization array on amniocentesis was normal in both cases. Exome sequencing identified a variation p.(Ser1275Thr) and p.(Ser1275Arg) in fetus 1 and fetus 2 in the FLT4 gene, respectively. A de novo mutation at the same codon was reported in prenatal literature suggesting possible genotype phenotype correlation. CONCLUSIONCystic hygroma/hydrops fetalis are possible manifestations of several disorders. This study illustrates how the integration of exome sequencing in prenatal clinical practice can facilitate the diagnosis and genetic counseling of heterogeneous developmental affections.
Solitary intestinal fibromatosis (SIF) is rare. Only 16 cases have been described in the new-born and infancy. We describe a new case of SIF with an unusual presentation including abnormal antenatal ...echographic findings. SIF was diagnosed at 2 months age when the child developed an intestinal obstruction. Differential diagnosis and review of literature are discussed. This lesion has an excellent prognosis when it is completely excised.
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