Nicole Morichon-Delvallez

Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development

Background: The acronym CHARGE refers to a non-random cluster of malformations including coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies. This set of multiple congenital anomalies is frequent, despite rare patients with normal intelligence, and prognosis remains poor. Recently, CHD7 gene mutations have been identified in CHARGE patients; however, the function of CHD7 during development remains unknown. Methods: We studied a series of 10 antenatal cases in whom the diagnosis of CHARGE syndrome was suspected, considering that a careful pathological description would shed light on the CHD7 function during development. CHD7 sequence analysis and in situ hybridisation were employed. Results: The diagnosis of CHARGE syndrome was confirmed in all 10 fetuses by the identification of a CHD7 heterozygous truncating mutation. Interestingly, arhinencephaly and semi-circular canal agenesis were two constant features which are not included in formal diagnostic criteria so far. In situ hybridisation analysis of the CHD7 gene during early human development emphasised the role of CHD7 in the development of the central nervous system, internal ear, and neural crest of pharyngeal arches, and more generally showed a good correlation between specific CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome. Conclusions: These results allowed us to further refine the phenotypic spectrum of developmental anomalies resulting from CHD7 dysfunction.

Functional disomy of the Xq28 chromosome region

We report on two patients, a boy and a girl, with an additional Xq28 chromosome segment translocated onto the long arm of an autosome. The karyotypes were 46,XY,der(10)t(X;10)(q28;qter) and 46,XX,der(4)t(X;4)(q28;q34), respectively. In both cases, the de novo cryptic unbalanced X-autosome translocation resulted in a Xq28 chromosome functional disomy. To our knowledge, at least 17 patients with a distal Xq chromosome functional disomy have been described in the literature. This is the third report of a girl with an unbalanced translocation yielding such a disomy. When the clinical features of both patients are compared to those observed in patients reported in the literature, a distinct phenotype emerges including severe mental retardation, facial dysmorphic features with a wide face, a small mouth and a thin pointed nose, major axial hypotonia, severe feeding problems and proneness to infections. A clinically oriented FISH study using subtelomeric probes is necessary to detect such a cryptic rearrangement.

Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature

The prenatal diagnosis of an 8p23.1 deletion is reported. The diagnosis was ascertained at 22 weeks of gestation because of the discovery of a diaphragmatic hernia at ultrasound. Following cytogenetic studies and counselling, the pregnancy was terminated. An autopsy confirmed the presence of a diaphragmatic hernia and revealed also the existence of an atrio‐ventricular canal (AVC) and an atrial septal defect (ASD). The clinical features of this antenatally diagnosed case are compared with those observed in 16 previously reported cases with an identical deletion of the short arm of chromosome 8. This suggests that a deletion 8p23.1 should be considered whenever a diaphragmatic hernia and/or an AVC is detected on ultrasound. Copyright

Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature

The prenatal diagnosis of a 1p36 deletion is reported. The pregnancy was ascertained at 24 weeks of gestation because of the discovery of multiple malformations at ultrasound including hypotelorism, moderate cerebral ventricular dilatation and Ebstein anomaly with secondary cardiac failure. Following cytogenetic studies and counselling, the pregnancy was terminated and a fetal autopsy performed. The phenotype of this antenatally‐diagnosed case is compared with the clinical features of 44 previously reported cases with an identical deletion of the short arm of chromosome 1p36. Copyright

Holoprosencephaly and sacral agenesis in a fetus with a terminal deletion 7q36-->7qter.

We describe here a fetus with holoprosencephaly and signs of caudal deficiency sequence. Chromosome examination showed a de novo balanced reciprocal translocation (7;22) (q36;q11) with loss of the derivative chromosome 22 in 50% of the cells examined. The present report and available published data indicate that the terminal region of the long arm of chromosome 7 contains genes implicated in the development of the central nervous system and the caudal region.

Familial interstitial Xq27.3q28 duplication encompassing the FMR1 gene but not the MECP2 gene causes a new syndromic mental retardation condition.

X-linked mental retardation is a common disorder that accounts for 5–10% of cases of mental retardation in males. Fragile X syndrome is the most common form resulting from a loss of expression of the FMR1 gene. On the other hand, partial duplication of the long arm of the X chromosome is uncommon. It leads to functional disomy of the corresponding genes and has been reported in several cases of mental retardation in males. In this study, we report on the clinical and genetic characterization of a new X-linked mental retardation syndrome characterized by short stature, hypogonadism and facial dysmorphism, and show that this syndrome is caused by a small Xq27.3q28 interstitial duplication encompassing the FMR1 gene. This family broadens the phenotypic spectrum of FMR1 anomalies in an unexpected manner, and we suggest that this condition may represent the fragile X syndrome «contre-type».

Array-based comparative genomic hybridization identifies a high frequency of copy number variations in patients with syndromic overgrowth

Overgrowth syndromes are a heterogeneous group of conditions including endocrine hormone disorders, several genetic syndromes and other disorders with unknown etiopathogenesis. Among genetic causes, chromosomal deletions and duplications such as dup(4)(p16.3), dup(15)(q26qter), del(9)(q22.32q22.33), del(22)(q13) and del(5)(q35) have been identified in patients with overgrowth. Most of them, however, remain undetectable using banding karyotype analysis. In this study, we report on the analysis using a 1-Mb resolution array-based comparative genomic hybridization (CGH) of 93 patients with either a recognizable overgrowth condition (ie, Sotos syndrome or Weaver syndrome) or an unclassified overgrowth syndrome. Five clinically relevant imbalances (three duplications and two deletions) were identified and the pathogenicity of two additional anomalies (one duplication and one deletion) is discussed. Altered segments ranged in size from 0.32 to 18.2 Mb, and no recurrent abnormality was identified. These results show that array-CGH provides a high diagnostic yield in patients with overgrowth syndromes and point to novel chromosomal regions associated with these conditions. Although chromosomal deletions are usually associated with growth retardation, we found that the majority of the imbalances detected in our patients are duplications. Besides their importance for diagnosis and genetic counseling, our results may allow to delineate new contiguous gene syndromes associated with overgrowth, pointing to new genes, the deregulation of which may be responsible for growth defect.

Prenatal diagnosis of a satellited non‐acrocentric chromosome derived from a maternal translocation (10;13)(p13;p12) and review of literature

We identified a familial balanced translocation involving chromosomes 10 and 13 through the finding of a satellited 10p chromosome in a fetus. The phenotype of two unbalanced products of the translocation resulting in pure monosomy 10p13 and trisomy 10p13 is described. This familial case and two of our unreported cases are discussed in the light of other prenatal observations with satellited non‐acrocentric chromosomes reported in the literature. Copyright

Gestational age-related reference values for amniotic fluid organic acids.

Normative data for amniotic fluid (AF) levels of organic acids at different gestational ages are lacking. They can provide a useful framework to investigate the accuracy of prenatal diagnosis for organic acidemias.

Maternal uniparental heterodisomy of chromosome 17 in a patient with nephropathic cystinosis

We report maternal uniparental disomy of chromosome 17 (mat UPD17) in a 2.5-year-old girl presenting infantile cystinosis. This patient was homozygous for the 57 kb deletion encompassing the CTNS gene, frequently found in patients from the European origin. The probands mother was heterozygous for the deletion and the father did not carry the deletion. We carried out haplotype analysis with polymorphic markers spanning the whole chromosome 17. Informative markers showed the presence of two maternal alleles but no paternal allele for regions spanning the 17q arm and the proximal half of 17p, and only one maternal allele on the distal 17p arm. As deletion of half of 17p is probably not viable, these results suggest mat UPD17 with heterodisomy of 17q and proximal 17p and isodisomy of distal 17p. This is the first demonstration of mat UPD17, in particular of isodisomy 17p, in cystinosis.