Browsing by Author "Castedo, S."
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- Classification of the dup 15q13.3 CNV: A National data collectionPublication . Sousa, A.; Serafim, S.; Santos, R.; Custódio, S.; Ávila, M.; Dupont, J.; Dias P, P.; Moldovan, O.; Melo, J.; Ferreira, S.; Pires, L.; Leão, M.; Sá, S.; Prior, C.; Alves, C.; Barreta, A.; Tarelho, A.; Marques, B.; Pedro, S.; Lopes, F.; Maciel, P.; Correia, H.; Dória, S.; Rendeiro, P.; Castedo, S.; Carreira, I.; Sousa, A.B.Introduction: The proximal region 15q11q14 is one of the most unstable regions in the human genome, with six recognizable break points (BP1-BP6). In 15q13.3 there is a recurrent small CNV (BP4-BP5) consisting of a 350-680 Kb duplication, encompassing the CHRNA7 gene, which encodes the alpha 7 subunit of the neuronal nicotinic acetylcholine receptor. Although microdeletions of CHRNA7 are known to cause intellectual disability and neuropsychiatric phenotypes with high penetrance, the patogenicity of CHRNA7 duplications remains unclear. Microduplication 15q13.3 seems to be associated with a phenotypic spectrum of cognitive impairment and neuropsychiatric/neurobehavioral disorders. However, the penetrance of this CNV is considered incomplete since it is present in clinically unaffected individuals in the general population and it is frequently inherited from apparently clinically normal parents. Nonetheless, some pedigree studies have found a history of neuropsychiatric problems among carrier family members. This study aimed at re-evaluating the dup 15q13.3 CNV in national laboratories. Materials and Methods: Our study collected data on 15q13.3 microduplications in eight Portuguese genetics laboratories, among subjects referred for microarray. Results: Here we present a total of seventeen cases with dup 15q13.3. The subjects had somewhat variable phenotypes, with a bias towards developmental delay and autism spectrum disorders. Inheritance was established for eight of the subjects, and the majority originated from the father. We had no access to clinical data on carrier parents. No de novo CNV was found. All laboratories involved classified this variant as of uncertain significance. Discussion/Conclusion: To better determine whether this CNV is benign or pathogenic, careful characterization of patient and control cohorts must be performed, including detailed patient phenotyping, inheritance, clinical evaluation of carrier parents, prevalence in controls, as well as genetic functional studies. We strongly support the creation of a national database for uncertain CNVs in order to clarify the relevance of these recurrent findings, allowing a definitive classification in either pathogenic or benign.
- Microarray in clinical practice – utility vs complexity. Mixed phenotype of duplication 15q11.2q13.1 and deletion 16p11.2Publication . Antunes, Diana; Rodrigues, M.I.; Carvalho, I.; Freixo, J.P.; Marques, B.; Pedro, S.; Kay, T.; Correia, H.; Castedo, S.; Nunes, L.Introduction: There’s a consensus to perform chromosomal microarray technique as first-tier clinical diagnostic test for individuals with developmental disabilities. However, given the complexity of clinical presentations, often several diagnostic methods are held before conducting microarray. Method: We report the case of a 5 year-old boy referred to Medical Genetics due to short stature, developmental disabilities and facial dysmorphic features. He was born from eutocic delivery after an uneventful pregnancy. He had psychomotor milestones delayed like sitting at 9 months and walking at 24 months, holding an immature broad-based gait. There was history of learning difficulties from both parents, and the mother has also short stature. On examination it was noted some facial dysmorphic features like high forehead, conical canines and rarefaction of the distal portion of the eyebrows. Due to the history of an episode of transient ataxia, and suspicion of an inherited metabolic disorder, he had already performed various analytical and imaging screenings, all normal. Results: Chromosomal microarray analysis revealed two pathogenic Copy Number Variants (CNV’s): 16p11.2 deletion and 15q11.2q13.1 duplication. The 15q11q13 microduplication syndrome (OMIM # 608636) is a very rare clinical entity with about 30 reported cases with maternal origin, and it is characterized by neurobehavioral disorder, hypotonia, cognitive impairment, epilepsy and short stature. The 16p11.2 microdeletion syndrome (OMIM # 613444) is also a rare clinical entity, with high penetrance, associated with obesity and developmental disabilities. Discussion: Despite the unquestionable utility of microarray, the correlation of the CNV's with the phenotype is often difficult by the rarity of these new microdeletion/duplication clinical entities. In this case the interpretation has increased difficulty because of the simultaneous existence of two distinct clinical entities. Segregation studies, which in the first step include parental analysis, are essential for genetic counseling and determining the risk of recurrence but also for a more accurate correlation genotype-phenotype.