Genetic investigation of syndromic forms of obesity

Carvalho, Laura Machado Lara; D’Angelo, Carla Sustek; Villela, Darine; Costa, Silvia Souza da; Jorge, Alexander A L; Silva, Israel Tojal da; Scliar, Marília de Oliveira; Chaves, Luiza Dias; Krepischi, Ana Cristina Victorino; Koiffmann, Célia Priszkulnik; Rosenberg, Carla

doi:10.1038/s41366-022-01149-5

Cited by 9 publications

(4 citation statements)

References 22 publications

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“…Patients 7 and 11 from the study of Fliedner et al (2020) also had obesity, but Patient 11 carried a SCAF4 VUS. Obesity is a common feature and has a high prevalence among people with cognitive impairment (Carvalho et al, 2022; Emerson et al, 2016; Hsieh et al, 2014; Melville et al, 2008). There are many factors that may contribute to this higher prevalence in people with ID, such as low levels of physical activity, poor nutritional habits (Melville et al, 2017), and the use of psychiatric drugs (de Winter et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

SCAF4‐related syndromic intellectual disability

Carvalho

Pinto

Scliar

et al. 2022

American J of Med Genetics Pt A

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The causal link between variants in the SCAF4 gene and a syndromic form of intellectual disability (ID) was established in 2020 by Fliedner et al. Since then, no additional cases have been reported. We performed exome sequencing in a 16-year-old Brazilian male presenting with ID, epilepsy, behavioral problems, speech impairment, facial dysmorphisms, heart malformations, and obesity. A de novo pathogenic variant [SCAF4(NM_020706.2):c.374_375dup(p.Glu126LeufsTer20)] was identified. This is the second study reporting the involvement of SCAF4 in syndromic ID, and the description of the patient's clinical features contributes to defining the phenotypic spectrum of this recently described Mendelian disorder.

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Section: Discussionmentioning

confidence: 99%

SCAF4‐related syndromic intellectual disability

Carvalho

Pinto

Scliar

et al. 2022

American J of Med Genetics Pt A

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“…Exome sequencing was carried out on the two siblings and both parents, with libraries produced by Agilent V7 capture kit and sequenced on the NovaSeq6000 150bpPE platform (IB‐USP). Sequencing data were processed using a GATK‐based pipeline as previously described (Carvalho et al, 2022). All KNL1 gene nomenclature is based on RefSeq: NM_170589.4.…”

Section: Methodsmentioning

confidence: 99%

A novel KNL1 intronic splicing variant likely destabilizes the KMN complex, causing primary microcephaly

Fellows,

Tolezano,

Pires

et al. 2023

American J of Med Genetics Pt A

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Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by head circumference of at least two standard deviations below the mean. Biallelic variants in the kinetochore gene KNL1 is a known cause of MCPH4. KNL1 is the central component of the KNL1–MIS12–NSL1 (KMN) network, which acts as the signaling hub of the kinetochore and is required for correct chromosomal segregation during mitosis. We identified biallelic KNL1 variants in two siblings from a non‐consanguineous family with microcephaly and intellectual disability. The two siblings carry a frameshift variant predicted to prematurely truncate the transcript and undergo nonsense mediated decay, and an intronic single nucleotide variant (SNV) predicted to disrupt splicing. An in vitro splicing assay and qPCR from blood‐derived RNA confirmed that the intronic variant skips exon 23, significantly reducing levels of the canonical transcript. Protein modeling confirmed that absence of exon 23, an inframe exon, would disrupt a key interaction within the KMN network and likely destabilize the kinetochore signaling hub, disrupting mitosis. Therefore, this splicing variant is pathogenic and, in trans with a frameshift variant, causes the MCPH phenotype associated with KLN1. This finding furthers the association of splicing variants as a common pathogenic variant class for KNL1.

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“…Many researchers reported that about 9 of the exome sequencing trios associated genes are known to cause mental retardation and development abnormality were detected in the examined patient and there are 2 specific genes that have a direct correlation with obesity (37).…”

Section: The Role Of Genetics In Obesitymentioning

confidence: 99%

Review of literature: Etiology of obesity, risk factors, and the role of genetics

Abdullah¹

2022

GSC Biol. Pharm. Sci.

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Obesity is considered one of the global most significant public problem as it has been associated with different diseases and even death. It is an excess accumulation of fat in the body as a result of increase calorie intake compared to energy expenditure. It is considered as multifactorial condition as many factors play role in its occurrence including genetic susceptibility, external environmental factors, individual attitude. The exact etiology of obesity is intermingled with different factors and nowadays because of development of different aspects of life, sedentary life style dominates the social communities, reduced physical activities, all these factors can enhance the risk of obesity. Furthermore, disturbances of the endocrine system like Cushing’s syndrome, hypothyroidism, diabetes type II. The genetic obesity it will be divided into two groups: 1) The monogenic type, the Poly genic type, syndrome associated obesity. Many individuals are suffering from obesity because of different genes that they already have which encourage them to high calorie diet with more food consumption, unlimited and uncontrolled food intake together with reduced physical activity. In conclusion the etiology, risk factors, as well as genetic susceptibility all are combined and correlated to each other as they may act separately or together to induce onset of obesity. The physical exercise and energy expenditure are having the key role., in addition to endocrine hormonal disturbances.

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Genetic investigation of syndromic forms of obesity

Cited by 9 publications

References 22 publications

SCAF4‐related syndromic intellectual disability

SCAF4‐related syndromic intellectual disability

A novel KNL1 intronic splicing variant likely destabilizes the KMN complex, causing primary microcephaly

Review of literature: Etiology of obesity, risk factors, and the role of genetics

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