Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Khattabi, Laïla El; Guimiot, Fabien; Pipiras, Eva; Andrieux, Joris; Baumann, Clarisse; Bouquillon, Sonia; Delezoïde, Anne Lise; Delobel, Bruno; Démurger, Florence; Dessuant, Hélène; Drunat, Séverine; Dubourg, Christelle; Dupont, Céline; Faivre, Laurence; Holder‐Espinasse, Muriel; Jaillard, Sylvie; Journel, Hubert; Lyonnet, Stanislas; Malan, Valérie; Masurel, Alice; Marle, Nathalie; Missirian, Chantal; Moerman, Alexandre; Moncla, Anne; Odent, Sylvie; Palumbo, Orazio; Palumbo, Pietro; Ravel, Aimé; Romana, Serge; Tabet, Anne Claude; Valduga, Mylène; Vermelle, Marie; Carella, Massimo; Dupont, Jean Michel; Verloès, Alain; Benzacken, Brigitte; Delahaye, Andrée

doi:10.1038/ejhg.2014.230

Cited by 34 publications

(21 citation statements)

References 51 publications

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“…Macrocephaly and tall stature and/or obesity are shared physical findings in some patients compatible with a contribution of the genomic region to growth regulation. El Khattabi et al suggested an involvement of the MCHR2 and SIM1 genes in behavioural disorders and SIM1 in obesity [19]. Both genes are not located within the deleted region of our patient.…”

Section: Discussionmentioning

confidence: 52%

“…[19] and Le Caignec et al [20] reported on patients with mostly larger heterozygous deletions in 6q16 (in a range between 1.7 and 14 Mb) which do not allow specific phenotype-genotype correlations. However, their patients, the patients summarized in Table 1 and our patient share phenotypic findings such as hypotonia, intellectual disability, developmental delay as well as autistic features or behavioural anomalies reminiscent of ASD.…”

Section: Discussionmentioning

confidence: 99%

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Autism and intellectual disability in a patient with two microdeletions in 6q16: a contiguous gene deletion syndrome?

et al. 2016

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BackgroundCopy number variations play a significant role in the aetiology of developmental disabilities including non-syndromic intellectual disability and autism.Case presentationWe describe a 19-year old patient with intellectual disability and autism for whom chromosomal microarray (CMA) analysis showed the unusual finding of two de novo microdeletions in cis position on chromosome 6q16.1q16.2 and 6q16.3. The two deletions span 10 genes, including FBXL4, POU3F2, PRDM13, CCNC, COQ3 and GRIK2. We compared phenotypes of patients with similar deletions and looked at the involvement of the genes in neuronal networks in order to determine the pathogenicity of our patient’s deletions.ConclusionsWe suggest that both deletions on 6q are causing his disease phenotype since they harbour several genes which are implicated in pathways of neuronal development and function. Further studies regarding the interaction between PRDM13 and GRIK2 specifically may be interesting.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Autism and intellectual disability in a patient with two microdeletions in 6q16: a contiguous gene deletion syndrome?

et al. 2016

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“…Although a variety of deletions have been reported to cause Prader-Willi related phenotypes, the most common PWL deletion is the 6q16 deletion comprising the bHLH-PAS family transcription factor SIM1 [20-22]. Sim1 heterozygous mice display hyperphagic obesity and reduced oxytocin expression in the hypothalamus [23,24].…”

Section: Discussionmentioning

confidence: 99%

Zebrafish Models of Prader-Willi Syndrome: Fast Track to Pharmacotherapeutics

et al. 2016

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Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder characterized by an insatiable appetite, leading to chronic overeating and obesity. Additional features include short stature, intellectual disability, behavioral problems and incomplete sexual development. Although significant progress has been made in understanding the genetic basis of PWS, the mechanisms underlying the pathogenesis of the disorder remain poorly understood. Treatment for PWS consists mainly of palliative therapies; curative therapies are sorely needed. Zebrafish, Danio rerio, represent a promising way forward for elucidating physiological problems such as obesity and identifying new pharmacotherapeutic options for PWS. Over the last decade, an increased appreciation for the highly conserved biology among vertebrates and the ability to perform high-throughput drug screening has seen an explosion in the use of zebrafish for disease modeling and drug discovery. Here, we review recent advances in developing zebrafish models of human disease. Aspects of zebrafish genetics and physiology that are relevant to PWS will be discussed, and the advantages and disadvantages of zebrafish models will be contrasted with current animal models for this syndrome. Finally, we will present a paradigm for drug screening in zebrafish that is potentially the fastest route for identifying and delivering curative pharmacotherapies to PWS patients.

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“…However, some mutations of SIM1 have incomplete penetrance and variable phenotype [57]. The similar phenotype between patients with SMI1 and MC4-R deficiency suggests that some effects of SIM1 are mediated by altered melanocortin signaling.…”

Section: Sim1 Deficiencymentioning

confidence: 99%

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Stagi¹,

Bianconi²,

Sammarco³

et al. 2017

Adiposity - Omics and Molecular Understanding

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Historically, some genetic syndromes and monogenic forms of obesity have been identified by clinical features and by sequencing candidate genes in patients with severe obesity. The phenotypic expression of genetic factors involved in obesity is variable, thereby allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. Many of the findings emerged from studying families who displayed a classical Mendelian pattern of inheritance. On the contrary, patients with syndromic obesity show a various degree of intellectual disability, different dysmorphic features, and organ-specific abnormalities. But to date, not all involved genes have been identified so far. New diagnostic tools, such as genome-wide studies, array CGH, and whole-exome sequencing, have highlighted more complex models of inheritance, and even more candidate genes were identified. This increase of knowledge may provide insights into the mechanisms involved in the regulation of body weight and finally lead to specific treatments. In these patients, hyperphagia is often a primary phenotypic component. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present today with a lack of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. We have evaluated retrospectively the literature data on weight, body mass index (BMI), clinical features, treatments, and treatment response in pediatric patients with forms of genetic obesity. However, this chapter provides an updated picture of emerging knowledge outlined by the more comprehensive genetic approaches, trying to outline more candidate genes for these forms of genetic obesity. Relevant papers will be identified through systematic searches of the PubMed, EMBASE and Cochrane databases. All published studies in the English language concerning these disorders will be evaluated. Keywords in the

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Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Cited by 34 publications

References 51 publications

Autism and intellectual disability in a patient with two microdeletions in 6q16: a contiguous gene deletion syndrome?

Autism and intellectual disability in a patient with two microdeletions in 6q16: a contiguous gene deletion syndrome?

Zebrafish Models of Prader-Willi Syndrome: Fast Track to Pharmacotherapeutics

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

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