Genetic evaluation of patients with Alström syndrome in the Polish population

Zmysłowska, Agnieszka; Borowiec, Maciej; Antosik, Karolina; Płoski, Rafał; Ciechanowska, Marta; Iwaniszewska, Barbara; Jakubiuk‐Tomaszuk, Anna; Jańczyk, Wojciech; Krawczyński, M; Salmonowicz, B.; Stelmach, Małgorzata; Młynarski, Wojciech

doi:10.1111/cge.12656

Cited by 18 publications

(12 citation statements)

References 14 publications

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“…If we assume that amongst all patients with MD in Poland GCK ‐MODY would constitute 40%, than the population‐wide estimate would reach 172 cases per million. This is most likely the lower bound of MD prevalence as it excludes patients with syndromic diabetes described in previous studies . A potential source of bias under this protocol is that we did not attempt to perform a population‐wide screening, but relied on the pediatric diabetologists to perform initial screening and evaluation.…”

Section: Discussionmentioning

confidence: 99%

“…To mitigate this we are continuously reevaluating our group for patients with negative results of genetic testing or discrepant phenotypes . We also did not included syndromic diabetes as they were described in earlier reports, but as those syndromes have low prevalence (0.29/100 000 children in 2015) the estimated MD prevalence would not change greatly—MD prevalence with syndromic diabetes would reach 7.81/100 000 children.…”

Section: Discussionmentioning

confidence: 99%

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Monogenic diabetes prevalence among Polish children-Summary of 11 years-long nationwide genetic screening program

et al. 2017

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Background Estimated monogenic diabetes (MD) prevalence increases as screening programs proceeds. Objective To estimate prevalence of MD among Polish children. Subjects Patients and their family members suspected of suffering from MD (defined as causative mutation in one of the Maturity Onset Diabetes of the Young or permanent neonatal diabetes mellitus genes) were recruited between January 2005 and December 2015. Methods Nationwide prevalence was estimated based on data from 6 administrative provinces (out of 16 in Poland) with high referral rates of patients (>10 per 100 000 children). Results During the analysis, probands from 322 of 788 screened families tested positive yielding a total of 409 children and 299 family members with MD. An average of 70 probands/year were referred. Screening success rate reached 40% over the study period. We estimated the prevalence of MD in 2015 to 7.52/100 000 children (1 in 13 000). The most frequent MODY in this group was GCK‐ MODY (6.88/100 000). The prevalence estimates increased nearly 2‐fold since our report in 2011 (4.4/100 000). However, the figure reached a plateau because of screening saturation in 2014 what was also proven by lowering of the median age of diagnosis lowered in time (R = −0.73, P = .0172) along with shortening of the delay between clinical and genetic diagnosis (R = −0.65, P = .0417). Conclusions The screening for childhood MD in Poland reached a plateau phase after 10 years showing a stable prevalence estimate. The true frequency of MD in the overall population may be higher given later onset of reportedly more frequent types of MD than GCK ‐MODY.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Monogenic diabetes prevalence among Polish children-Summary of 11 years-long nationwide genetic screening program

et al. 2017

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“…About 15% of the Alström patients do not carry any mutation in the exonic region of ALMS1 gene which makes the confirmation of clinical diagnosis difficult (Ozanturk et al, 2015). So far, majority of these studies have been published on sporadic AS cases (Kilinc et al, 2018, Lindsey et al, 2017, Zmyslowska et al, 2016). On the other hand, studying familial forms of AS presents a good opportunity to identify both ALMS1 mutations and their mode of inheritance.…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

Kamal

Sahly

Banaganapalli

et al. 2020

Saudi Journal of Biological Sciences

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Alström syndrome (AS, OMIM ID 203800) is a rare childhood multiorgan disorder, which is widely studied in non-Arab ethnic patients. The clinical and molecular basis of AS and the mode of disease inheritance in consanguineous Arab populations is not well investigated. Therefore, to identify the molecular basis of AS in familial forms, the present study performed whole exome sequencing of 5 AS patients belonging to 2 different Bedouin families from Saudi Arabia. The present study identified the AS causative rare biallelic mutations in ALMS gene:T376S in exon 5 and S909* in exon 8 for family A and an R2721* in exon 10 (R2721*) for family B. ALMS1 targeted genetic sequencing of healthy population controls and family members has confirmed its extremely rare frequency and autosomal recessive mode of inheritance. The truncating mutations S909* and R2721* could cause the loss of CC domains and ALMS motif on C-terminal end of the protein and creates unstable protein, which eventually undergoes intracellular degradation. The premature protein truncating mutations described in our study may eventually provide further insight into the functional domains of the ALMS1 protein and contribute to the understanding of the phenotypic spectrum of AS. Whole exome sequencing based molecular diagnosis is expected to rule out ambiguity surrounding clinical diagnosis of suspected AS cases.

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“…The diagnostic difficulties in the identification of the BBS patients are related not only to the number of pathogenic variants in many genes, which have so far been discovered in more than 20 [8] and the postulated model of triallelic inheritance [9], but also to overlapping clinical features of the disease with other ciliopathies with early obesity, such as Alstrom syndrome [10]. Therefore, further studies seem to be important for understanding the causes of the disease and thus to make an earlier accurate diagnosis and propose not only symptomatic but also causal treatment, including gene therapy [8].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing in the Diagnosis of Patients with Bardet–Biedl Syndrome—New Variants and Relationship with Hyperglycemia and Insulin Resistance

Jeziorny

Antosik

Jakiel

et al. 2020

Genes

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Bardet-Biedl syndrome (BBS) is a rare autosomal recessively inherited disease with major clinical symptoms such as: obesity, retinal degeneration, polydactyly and renal abnormalities. The aim of the study was to assess the spectrum of gene variants among patients with BBS, identified on the basis of nationwide genetic studies of monogenic diabetes in Polish population. Out of 575 patients enrolled for genetic testing from February 2017 to July 2019, 25 patients with a clinical suspicion of BBS were selected. The identification of pathogenic variants was performed by using targeted next-generation sequencing (NGS) on Illumina NextSeq 550 platform involving the SureSelect assay (Agilent, Santa Clara, CA, USA). BBS was genetically confirmed in 10 of 25 suspected patients. In patients, 14 different variants were found in six genes, mainly in BBS9 and BBS10 gene, including two novel variants. A strong association between hyperglycemia and insulin resistance in patients and the presence of variants in BBS9 gene was observed. Identification of 14 variants, including two new mutations using the NGS method, is the first molecular characteristic of Polish patients with Bardet–Biedl syndrome. It gives hope for earlier proper diagnosis of BBS in future patients selected from children with early childhood obesity and their medical multidisciplinary care.

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Genetic evaluation of patients with Alström syndrome in the Polish population

Cited by 18 publications

References 14 publications

Monogenic diabetes prevalence among Polish children-Summary of 11 years-long nationwide genetic screening program

Monogenic diabetes prevalence among Polish children-Summary of 11 years-long nationwide genetic screening program

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

Next-Generation Sequencing in the Diagnosis of Patients with Bardet–Biedl Syndrome—New Variants and Relationship with Hyperglycemia and Insulin Resistance

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