Characterization of a Pathogenic Variant in the ABCD1 Gene Through Protein Molecular ModelingRead the full article
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Candidate Genes Associated with Delayed Neuropsychomotor Development and Seizures in a Patient with Ring Chromosome 20
Ring chromosome 20 (r20) is characterized by intellectual impairment, behavioral disorders, and refractory epilepsy. We report a patient presenting nonmosaic ring chromosome 20 followed by duplication and deletion in 20q13.33 with seizures, delayed neuropsychomotor development and language, mild hypotonia, low weight gain, and cognitive deficit. Chromosomal microarray analysis (CMA) enabled us to restrict a chromosomal segment and thus integrate clinical and molecular data with systems biology. With this approach, we were able to identify candidate genes that may help to explain the consequences of deletions in 20q13.33. In our analysis, we observed five hubs (ARFGAP1, HELZ2, COL9A3, PTK6, and EEF1A2), seven bottlenecks (CHRNA4, ARFRP1, GID8, COL9A3, PTK6, ZBTB46, and SRMS), and two H-B nodes (PTK6 and COL9A3). The candidate genes may play an important role in the developmental delay and seizures observed in r20 patients. Gene ontology included microtubule-based movement, nucleosome assembly, DNA repair, and cholinergic synaptic transmission. Defects in these bioprocesses are associated with the development of neurological diseases, intellectual disability, neuropathies, and seizures. Therefore, in this study, we can explore molecular cytogenetic data, identify proteins through network analysis of protein-protein interactions, and identify new candidate genes associated with the main clinical findings in patients with 20q13.33 deletions.
Behçet Disease-Like Symptoms with a Novel COPA Mutation
COPA syndrome is a recently described autosomal dominant disorder with key immune dysregulation caused by defects within the COPA gene. These mutations lead to endoplasmic reticulum stress and autoimmune response with upregulation of Th17 cytokines. The clinical phenotype of COPA syndrome primarily comprised pulmonary disease, arthritis, and renal disease secondary to immune dysregulation, with onset of symptoms commonly in the first decade of life. Herein, we describe a family with an attenuated Behçet-like phenotype of COPA syndrome, further expanding the phenotypic understanding of this syndrome.
Chromosome 16p13.3 Contiguous Gene Deletion Syndrome including the SLX4, DNASE1, TRAP1, and CREBBP Genes Presenting as a Relatively Mild Rubinstein–Taybi Syndrome Phenotype: A Case Report of a Saudi Boy
The classic Rubinstein–Taybi syndrome Type 1 (RSTS1, OMIM 180849) is caused by heterozygous mutations or deletions of the CREBBP gene. Herein, we describe the case of a Saudi boy with chromosome 16p13.3 contiguous gene deletion syndrome (OMIM 610543) including the SLX4, DNASE1, TRAP1, and CREBBP genes, but presenting with a relatively mild RSTS1 syndrome phenotype. Compared with previously reported cases with severe phenotypes associated with 16p13.3 contiguous gene deletions, our patient had partial deletion of the CREBBP gene (with a preserved 5′ region), which might explain his relatively mild phenotype.
A Tanzanian Boy with Molecularly Confirmed X-Linked Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with classical features, which can be also recognised in a low resource setting. It had been described in various populations across the globe, but very few cases have been reported from Africa. In a boy with features of a progressive central nervous system condition and adrenal failure, ABCD1 gene screening was performed based on a clinical history and basic radiological features which were compatible with ALD. A common ABCD1 mutation was identified in this patient, which is the first report of genetically confirmed ALD in Sub-Saharan Africa. ALD is likely under recognised in those areas where there is no neurologist. This genetic confirmation widens geographical distribution of ABCD1-associated disease, and illustrates recognisability of this disorder, even when encountered in a low-resource environment.
Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome
Background. Oculofaciocardiodental (OFCD) syndrome is due to mutations in BCOR (BCL-6 corepressor). OFCD has phenotypic overlaps with PHACE syndrome (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac defects, Eye anomalies). Infantile hemangiomas are a key diagnostic criterion for PHACE, but not for OFCD. A previous study reported two cases of infantile hemangiomas in OFCD, but the authors could not exclude chance association. Case Presentation. We describe two novel cases of female patients (one initially diagnosed with PHACE syndrome), both of whom had infantile hemangiomas. Ophthalmological findings were consistent with oculofaciocardiodental (OFCD) syndrome. Upon genetic testing, these two females were determined to have X-linked BCOR mutations confirming OFCD syndrome diagnoses. Conclusion. These case reports add support to the hypothesis that infantile hemangiomas may be a feature of OFCD. BCOR may potentially be within a pathway of genes involved in PHACE syndrome and/or in infantile hemangioma formation.
Towards New Approaches to Evaluate Dynamic Mosaicism in Ring Chromosome 13 Syndrome
Individuals with ring chromosome 13 may show characteristics observed in a deletion syndrome and could present a set of dismorphies along with intellectual disability, according to chromosomal segments involved in the genetic imbalance. Nevertheless, ring anomalies likewise is called “dynamic mosaicism”, phenomena triggered by the inner instability concerning the ring structure, thus leading to the establishment of different cell clones with secondary aberrations. Phenotypic features, such as growth failure and other anomalies in patients with this condition have been associated with an inherent ring chromosome mitotic instability, while recent studies offer evidence on a role played by the differential loss of genes implicated in development. Here, we observed similar mosaicism rates and specific gene loss profile among three individuals with ring chromosome 13 using GTW-banding karyotype analyses along with FISH and CGH-array approaches. Karyotypes results were: patient 1—r(13)(p13q32.3), patient 2—r(13)(p11q33.3), and patient 3—r(13)(p12q31.1). Array-CGH has revealed qualitative genetic differences among patients in this study and it was elusive in precise chromosomal loss statement, ranging from 13 Mb, 6.8 Mb, and 30 Mb in size. MIR17HG and ZIC2 loss was observed in a patient with digital anomalies, severe growth failure, microcephaly and corpus callosum agenesis while hemizygotic EFNB2 gene loss was identified in two patients, one of them with microphtalmia. According to these findings, it can be concluded that specific hemizygotic loss of genes related to development, more than dynamic mosaicism, may be causative of congenital anomalies shown in patients with ring 13 chromosome.