Alström Syndrome: Mutation Spectrum of<i>ALMS1</i>

Marshall, Jan D.; Muller, Jean; Collin, Gayle B.; Milan, Gabriella; Kingsmore, Stephen F.; Dinwiddie, Darrell L.; Farrow, Emily; Miller, Neil; Favaretto, Francesca; Maffei, Pietro; Dollfus, Hélène; Vettor, Roberto; Naggert, Juergen K

doi:10.1002/humu.22796

Cited by 133 publications

(197 citation statements)

References 74 publications

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“…(Glu1493*) 61 NM_015120.4: c.7571_7572del;p. (His2524Argfs*11) 61 NGSY (AR) RP-2177 AlströmAlströmCRD, hearing loss, and dilated cardiomyopathy ALMS1 NM_015120.4:c.808C>T;p. (Arg270*) 31 NM_015120.4:c.11618_11619del;p.…”

Section: Resultsmentioning

confidence: 99%

“…(Arg270*) 31 NM_015120.4:c.11618_11619del;p. (Ser3873Tyrfs*19) 61 NGSna RP-2069 BBSBBSCRD, polydactyly, maturation and learning delay, obesity, and chronic renal failure IFT27 NM_006860.4:c.104A>G; p. (Tyr35Cys)NM_006860.4:c.350-2A>G NGSna RP-2167 BBSBBSCRD, obesity, polydactyly and brachydactyly, psychomotor and learning delay, and behaviour disorder BBS2 NM_031885.2:c.471G>A; Affecting 5′ splicing site 31 NM_031885.2:c.1237C>T; p.(Arg413*) 30 NGSna RP-2228 BBSBBSRP, ID, overweight since infancy, brachydactyly, chronic renal failure, and renal transplant BBS1 NM_024649.4:c.1645G>T; p.…”

Section: Resultsmentioning

confidence: 99%

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Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Sánchez‐Navarro

Silva

Blanco‐Kelly

et al. 2018

Sci Rep

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Inherited syndromic retinopathies are a highly heterogeneous group of diseases that involve retinal anomalies and systemic manifestations. They include retinal ciliopathies, other well-defined clinical syndromes presenting with retinal alterations and cases of non-specific multisystemic diseases. The heterogeneity of these conditions makes molecular and clinical characterization of patients challenging in daily clinical practice. We explored the capacity of targeted resequencing and copy-number variation analysis to improve diagnosis of a heterogeneous cohort of 47 patients mainly comprising atypical cases that did not clearly fit a specific clinical diagnosis. Thirty-three likely pathogenic variants were identified in 18 genes (ABCC6, ALMS1, BBS1, BBS2, BBS12, CEP41, CEP290, IFT172, IFT27, MKKS, MYO7A, OTX2, PDZD7, PEX1, RPGRIP1, USH2A, VPS13B, and WDPCP). Molecular findings and additional clinical reassessments made it possible to accurately characterize 14 probands (30% of the total). Notably, clinical refinement of complex phenotypes was achieved in 4 cases, including 2 de novo OTX2-related syndromes, a novel phenotypic association for the ciliary CEP41 gene, and the co-existence of biallelic USH2A variants and a Koolen-de-Vries syndrome–related 17q21.31 microdeletion. We demonstrate that combining next-generation sequencing and CNV analysis is a comprehensive and useful approach to unravel the extensive phenotypic and genotypic complexity of inherited syndromic retinopathies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Sánchez‐Navarro

Silva

Blanco‐Kelly

et al. 2018

Sci Rep

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“…The disease-cause variants are primarily clustered in exon 8, as our case, exon 10, and exon 16. Currently, 239 different ALMS1 mutations have been identified, the majority of which are nonsense and frameshift (insertions or deletions) mutations [1,6]. Our patient was hemi-/homozygous for a mutation of the ALMS1 gene in exon 8 (c8911C[T, p.Gln2971*).…”

Section: Discussionmentioning

confidence: 85%

“…Our patient was hemi-/homozygous for a mutation of the ALMS1 gene in exon 8 (c8911C[T, p.Gln2971*). To the best of our knowledge this mutation has not been reported before [6]. ALMS1 protein is located in centrosomes and ciliary basal bodies of most tissues affected in AS, explaining the wide range of phenotypical variability.…”

Section: Discussionmentioning

confidence: 86%

Follicular variant of papillary thyroid cancer in Alström syndrome

et al. 2015

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Alström syndrome (AS) is an autosomal recessive disorder, characterized by cone-rod dystrophy, sensorineural hearing loss, obesity, hyperinsulinemia with insulin resistance, type 2 diabetes mellitus and progressive pulmonary, hepatic and renal dysfunction. AS is caused by mutations in the ALMS1 gene, located on the short arm of chromosome 2. We report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma. To our knowledge this is the first association of AS with thyroid malignancy, among the approximately 450 cases reported since the first description of the syndrome. We conclude that papillary thyroid carcinoma should be considered in the differential diagnosis of thyroid nodules in patients with AS.

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“…The clinical features of these syndromes include obesity and developmental delay [5]. Examples are the Bardet–Biedl [19], Prader–Willi [20], and Alström [21] syndromes. These syndromes were earlier viewed as monogenic, but later studies pointed to a heterogeneous genetic background [4, 19, 20].…”

Section: Introductionmentioning

confidence: 99%

A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network

et al. 2016

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BackgroundObesity is heritable. It predisposes to many diseases. The objectives of this study were to create a compendium of genes relevant to feeding behavior (FB) and/or body weight (BW) regulation; to construct and to analyze networks formed by associations between genes/proteins; and to identify the most significant genes, biological processes/pathways, and tissues/organs involved in BW regulation.ResultsThe compendium of genes controlling FB or BW includes 578 human genes. Candidate genes were identified from various sources, including previously published original research and review articles, GWAS meta-analyses, and OMIM (Online Mendelian Inheritance in Man). All genes were ranked according to knowledge about their biological role in body weight regulation and classified according to expression patterns or functional characteristics. Substantial and overrepresented numbers of genes from the compendium encoded cell surface receptors, signaling molecules (hormones, neuropeptides, cytokines), transcription factors, signal transduction proteins, cilium and BBSome components, and lipid binding proteins or were present in the brain-specific list of tissue-enriched genes identified with TSEA tool. We identified 27 pathways from KEGG, REACTOME and BIOCARTA whose genes were overrepresented in the compendium. Networks formed by physical interactions or homological relationships between proteins or interactions between proteins involved in biochemical/signaling pathways were reconstructed and analyzed. Subnetworks and clusters identified by the MCODE tool included genes/proteins associated with cilium morphogenesis, signal transduction proteins (particularly, G protein–coupled receptors, kinases or proteins involved in response to insulin stimulus) and transcription regulation (particularly nuclear receptors). We ranked GWAS genes according to the number of neighbors in three networks and revealed 22 GWAS genes involved in the brain-specific PPI network. On the base of the most reliable PPIs functioning in the brain tissue, new regulatory schemes interpreting relevance to BW regulation are proposed for three GWAS genes (ETV5, LRP1B, and NDUFS3). ConclusionsA compendium comprising 578 human genes controlling FB or BW was designed, and the most significant functional groups of genes, biological processes/pathways, and tissues/organs involved in BW regulation were revealed. We ranked genes from the GWAS meta-analysis set according to the number and quality of associations in the networks and then according to their involvement in the brain-specific PPI network and proposed new regulatory schemes involving three GWAS genes (ETV5, LRP1B, and NDUFS3) in BW regulation. The compendium is expected to be useful for pathology risk estimation and for design of new pharmacological approaches in the treatment of human obesity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0466-2) contains supplementary material, which is available to authorized users.

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Alström Syndrome: Mutation Spectrum ofALMS1

Cited by 133 publications

References 74 publications

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

Follicular variant of papillary thyroid cancer in Alström syndrome

A compendium of human genes regulating feeding behavior and body weight, its functional characterization and identification of GWAS genes involved in brain-specific PPI network

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