Differentiating Alström from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing

Hellé, Sophie; Gyapay, Gábor; Duchatelet, Sabine; Mandel, Jean‐Louis; Dollfus, Hélène

doi:10.3109/13816810.2011.620055

Cited by 33 publications

(31 citation statements)

References 40 publications

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“…None of them presented with polydactyly. As previously suggested, 3 both, the absence of polydactyly and the prevalence of deafness in ALMS1-mutated patients, are keys for genotype-phenotype discrimination between ALMS and BBS mutated patients.…”

Section: Correlation Between Mutation Detection Efficiency and Clinicmentioning

confidence: 74%

“…25e27 The phenotypic overlap between BBS and ALMS seems to be larger than previously thought, as recently suggested with examples of Alström patients with mutations in BBS genes, 5 and the reverse situation, such as in our study, of ALMS1 mutations in patient with suspected BBS. 3 Lastly, no clearly pathogenic mutation was found in any NPHP or JBTS genes in the cohort.…”

Section: Mutation Load In Bbs and Other Targeted Genes: Importance Ofmentioning

confidence: 86%

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Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

et al. 2012

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BackgroundBardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alström syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (BBS1-BBS16) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly.MethodWe tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B.ResultsThis strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of ‘classical’ BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants.ConclusionThis strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.

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Section: Correlation Between Mutation Detection Efficiency and Clinicmentioning

confidence: 74%

Section: Mutation Load In Bbs and Other Targeted Genes: Importance Ofmentioning

confidence: 86%

Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

et al. 2012

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“…10 Normal mentation and lack of poly/syndactyly help to distinguish Alstrom syndrome from BBS, while deafness and the absence of spastic paraparesis help to differentiate Alstrom syndrome from Laurence-Moon.…”

Section: Discussionmentioning

confidence: 98%

Alstrom syndrome – a diagnosis revisited

Vusirikala

Rajkumar

Choudhary

et al. 2013

Diabetes & Vascular Disease

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A 34 year old male referred by ophthalmology to our diabetes clinic with poor metabolic control. He was diagnosed to have type 2 diabetes at the age of 27 years when he presented with abdominal pain and osmotic symptoms with an HbA 1c of 11.2 %. There was no family history of diabetes and he was diagnosed with hypertension at the age of 25 years along with a severe mixed dyslipidaemia. All investigations for secondary hypertension were negative.On physical examination, he was noted to be significantly overweight with a BMI of 36 kg/m 2 and central adiposity. He did not have any evidence of micro or macrovascular complications. He wore hearing aids in both ears and was noted to have nystagmus with perception of light in both eyes. He had normal anterior segments apart from bilateral early sub capsular cataracts with normal intraocular pressures. A fundus examination showed the presence of bilateral pigmentary retinopathy with a slightly pale optic disc. There was no evidence of poly-or syndactyly suggestive of BBS.His diabetes was initially treated with metformin and then pioglitazone. His glycaemic control continued to be suboptimal due to his poor diet and reduced mobility. He was intolerant to GLP-1 therapy and was eventually commenced on insulin.He was also treated with ezetimibe and nicotinic acid as he was intolerant to statins & fibrates. His liver enzymes were slightly abnormal with an isolated elevated γGT .There were no stigmata of chronic liver disease and an ultrasound scan was normal apart from fatty infiltration. He was also found to have hypogonadism and commenced on testosterone therapy.His prior history included poor vision since the age of 8 when he was registered blind. His vision continued to deteriorate and by the age of 12 he just had perception of light with sensorineural deafness diagnosed at fifteen. He was also previously considered to have ocular albinism. Various ocular diagnoses were suggested including the possibility of Usher's Syndrome (type 2). The diagnosis of Abstract Carl Henry Alstrom first described the syndrome in 1959. 1 It is a rare autosomal recessive, single gene, multi system disorder characterised by early onset retinal (progressive cone rod) dystrophy with profound visual loss, childhood obesity with insulin resistance, hyperinsulinaemia and diabetes, sensorineural hearing loss, dilated cardiomyopathy as well as progressive renal and hepatic dysfunction. We present a case of Alstrom syndrome diagnosed in a 34 year old male subject followed by a brief review of its clinical presentation

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“…Diagnosis is very difficult in early infancy, due to age-dependent typical features, often not evident until 6–8 years (Table 1). The identification of ALMS as a ciliary protein disorder explains the range of observed phenotypes and their similarity to other ciliopathies [4] such as Bardet-Biedl syndrome (BBS; OMIM #209900), a multi-systemic disease that comprises retinal dystrophy associated to obesity, polydactyly, renal malformations, hypogonadism, and cognitive impairment [5]. BBS is an autosomal recessive condition, although an oligogenic mode of inheritance has been shown in some families where three mutations at two BBS loci are found [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…To date, 18 genes (BBS1-18) are known to be associated with BBS [8], whereas only one gene has been identified for ALMS [5,9]. Nevertheless, overlapping phenotypes have been reported between ALMS and BBS [10-12].…”

Section: Introductionmentioning

confidence: 99%

Syndromic obesity: clinical implications of a correct diagnosis

et al. 2014

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BackgroundAlthough individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases.Case presentationThe patient was born at term after a pregnancy complicated by threatened miscarriage. A diagnosis of Bardet-Biedl syndrome (BBS; OMIM #209900) was made in another hospital when she was 8 years old, but other clinical problems emerged subsequently. She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophtalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern, was more suggestive for Alström syndrome (ALMS; OMIM #203800); consequently, a genetic study was performed. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]), which has not previously been described.ConclusionEarly onset of retinal degeneration associated with obesity represents a diagnostic challenge in paediatric and genetic practice, although the absence of skeletal abnormalities and developmental delay could help in addressing the clinical diagnosis. Confirmation of clinical suspicion by genetic analysis has been diriment in this case, since only a single gene is known to cause ALMS.

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Differentiating Alström from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing

Abstract: Ciliopathy genes sequencing can be very helpful in providing a timely diagnosis in this group of patients, hence appropriate genetic counselling for families and adequate medical follow-up for affected children.

Cited by 33 publications

References 40 publications

Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

Alstrom syndrome – a diagnosis revisited

Syndromic obesity: clinical implications of a correct diagnosis

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