Mileny E.S. Colovati

Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene

BackgroundThe majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature.ResultsWe report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15.DiscussionThis is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement.

Position effect modifying gene expression in a patient with ring chromosome 14

The clinical phenotype of patients with ring chromosomes usually reflects the loss of genomic material during ring formation. However, phenotypic alterations can also be found in the presence of complete ring chromosomes, in which the breakage and rejoining in terminal regions of both chromosome arms result in no gene loss. Here, we present a patient with a ring chromosome 14 that lost nothing but the telomeres. Since he and other patients with a similar chromosome abnormality present certain abnormal characteristics, we investigated the gene expression of eight chromosome 14 genes to find out whether the configuration of the ring had changed it, possibly producing some of these clinical features. The expression of these eight genes was studied by quantitative real-time polymerase chain reaction (qPCR) in the patient and in seven controls matched for gender and age. Two of them were found to be downregulated in the patient compared to the controls, indicating that his phenotype might be related to alterations in the expression of genes located in the abnormal chromosome, even when the copy number is normal. Thus, the phenotypic alterations found in the presence of complete ring chromosomes may be related to changes in the chromatin architecture, bringing about a change of expression by position effect. These results may explain some of the characteristics presented by our patient.

A novel de novo mutation in MYT1 , the unique OAVS gene identified so far

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.

Atypical 581-kb 22q11.21 Deletion in a Patient with Oculo-Auriculo-Vertebral Spectrum Phenotype.

The oculo-auriculo-vertebral spectrum (OAVS) is defined as a group of malformations involving the ears, mouth, mandible, eyes, and cervical spine. Establishing an accurate clinical diagnosis of OAVS is a challenge for clinical geneticists, not only because these patients display heterogeneous phenotypes, but also because its etiology encompasses environmental factors, unknown genetic factors and different chromosome aberrations. To date, several chromosomal abnormalities have been associated with the syndrome, most frequently involving chromosome 22. In the literature, six 22q11.2 microdeletions have been described within the same region, suggesting possible OAVS candidate genes in this segment. Here, we report on a patient with an ∼581-kb 22q11.21 deletion, detected by genomic array and MLPA. This is the 7th case described with OAVS and 22q deletion, suggesting that the 22q11.2 region may be related to the regulation of body symmetry and facial development.

Clinical and cytogenomic findings in OAV spectrum

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.

Wolf-Hirschhorn Syndrome with Epibulbar Dermoid: An Unusual Association in a Patient with 4p Deletion and Functional Xp Disomy

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene and multiple malformation syndrome that results from a deletion in the 4p16.3 region. We describe here a 6-month-old girl that presented with WHS features but also displayed unusual findings, such as epibulbar dermoid in the left eye, ear tags, and left microtia. Although on G-banding her karyotype appeared to be normal, chromosomal microarray analysis revealed an ∼13-Mb 4p16.3p15.33 deletion and an ∼9-Mb Xp22.33p22.31 duplication, resulting from a balanced maternal t(X;4)(p22.31;p15.33) translocation. The patient presented with functional Xp disomy due to an unbalanced X-autosome translocation, a rare cytogenetic finding in females with unbalanced rearrangements. Sequencing of both chromosome breakpoints detected no gene disruption. To the best of our knowledge, this is the first patient described in the literature with WHS and epibulbar dermoid, a typical characteristic of the oculoauriculovertebral spectrum (OAVS). Our data suggest that possible candidate genes for OAVS may have been deleted along with the WHS critical region.

Spinal muscular atrophy due to a “de novo” 1.3 Mb deletion: Implication for genetic counseling

We report a 3-year-old female with type I spinal muscular atrophy (SMA) born to a young and non-consanguineous couple. The child presented at two months of life with intense muscle weakness affecting predominantly proximal portions of the limbs, especially the legs, muscle hypotonia, fasciculation of the tongue, and severe respiratory muscle involvement. She remained in an intensive care unit with an assisted ventilation system from the fourth month of life. She died at 3 years of age from pulmonary infection. Molecular analysis confirmed the diagnosis of SMA but revealed that only the father was an asymptomatic carrier. Because SMN1 is mapped in a complex region containing repetitive elements due to an inverted duplication of approximately 500 kb, we carry out an SNP array and detected a 1.3 Mb deletion including the SMN1 and SMN2 genes that explain the disease.

Call for Nomination of Members of the International Standing Committee of Human Cytogenomic Nomenclature

The present Committee (Jaclyn Biegel, Myriam Chaabouni, Johan T. den Dunnen, Jin-Yeong Han, Nils Mandahl, Jean McGowan-Jordan, Kathleen W. Rao, Annet Simons) was elected in the fall of 2011, with Lisa Shaffer as Chair. The Committee elected a new Chair, Jean McGowan-Jordan, during their meeting in Seattle in 2012. Several new members of the Committee now need to be elected. To facilitate continuity and maintain geographic distribution, the Chair of the new Committee will remain, along with Nils Mandahl, Johan T. den Dunnen, and Jin-Yeong Han. New members from the Americas (2), Europe (1), Africa and Australia/New Zealand/Oceania (1) are therefore required. The nominations of potential new Committee members shall be by e-mail. Nominations for candidates including their name, affiliation, postal address and e-mail address should be e-mailed to the Chair at jordan@cheo.on.ca before February 15, 2018, after which the list of nominated candidates will be published with the call for voting. Ballots for voting can be requested from the Chair at jordan@cheo.on.ca after February 15, 2018, by including your name, affiliation, postal address, and e-mail. The election ballots with voting procedures will then be distributed after March 15, 2018, to the requested address. Instructions for returning the ballots will accompany the ballot requests. Published online: January 23, 2018

Deletion 21pterq22.11: Report of a Patient with Dysmorphic Features, Hypertonia, and Café-au-Lait Macules and Review of the Literature

Partial monosomy 21 results in a great variability of clinical features that may be associated with the size and location of the deletion. In this study, we report a 22-month-old girl who showed a 45,XX,add(12)(p13)dn,-21 karyotype. The final cytogenomic result was 45,XX,der(12)t(12;21)(p13;q22.11) dn,-21.arr[hg19] 21q11.2q22.11(14824453_33868129)×1 revealing a deletion from 21pter to 21q22.11. Clinical manifestation of the patient included hypertonia, a long philtrum, epicanthic folds, low-set ears, and café-au-lait macules - a phenotype considered as mild despite the relatively large size of the deletion compared to patients from the literature.

Miller-Dieker Syndrome due to a 5.5-Mb 17p Deletion in a 17;Y Pseudodicentric Chromosome

Miller-Dieker syndrome (MDS) is a contiguous gene deletion syndrome in which almost all patients present de novo 17p13.3 deletions. We report on a male infant with MDS and an unusual unbalanced translocation involving chromosomes Y and 17 that resulted in a large 5.5-Mb 17pterp13.2 deletion and a karyotype with 45 chromosomes. Apart from the deletion of the MDS critical region, the deletion of additional distal genes seemed to have no major influence on the patients phenotype, since he did not show any unusual clinical findings that are not commonly described in MDS patients.