Clinical diagnosis of Larsen syndrome, Stickler syndrome and Loeys-Dietz syndrome in a 19-year old male: a case report

Riise, Nina; Lindberg, B; Kulseth, Mari Ann; Fredwall, Svein O.; Lundby, Rigmor; Estensen, Mette E; Drolsum, Liv; Merckoll, Else; Krohg‐Sørensen, Kirsten; Paus, Benedicte

doi:10.1186/s12881-018-0671-0

Cited by 12 publications

(15 citation statements)

References 24 publications

(29 reference statements)

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“…NGS analysis and post-analytic assessment resulted in confirmation of a clinical diagnosis in 41 patients. In another patient, two separate HCTD were uncovered (Riise et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Diagnostics of Hereditary Connective Tissue Disorders by Genetic Next-Generation Sequencing

Pope

Ratajska

Johnsen

et al. 2019

Genetic Testing and Molecular Biomarkers

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Aims: This quality study aimed to review the indications, reports, and clinical consequences of 438 diagnostic next generation sequencing (NGS) gene panel analyses for hereditary connective tissue disorders (HCTD). Methods: Molecular analyses were retrieved from the laboratory database and patient journal and compared to clinical information in the requisition and journal, classified according to the Human Phenotype Ontology. Results: In 123 of 438 NGS analyses, 156 sequence variants were reported in 33 of 54 genes analyzed. NGS analyses and, in some cases, post-analytic assessment resulted in pathogenic variants in 41 (9%) and variants of uncertain significance in 83 (19%) of analyses. While cardiovascular abnormalities were the most common phenotype noted in requisitions, no specific organ system could be identified in which symptoms represent a preferable indication for the analysis. Certain health issues recorded in the journal were found to be frequently left out of requisitions. Conclusions: The interpretation of genetic sequence variants continues to be a significant challenge in HCTD. Although not associated with the highest diagnostic yield, cardiovascular disease and family history may be suitable indications for NGS due to the clinical consequences of the identification of a causative sequence variant for a vascular HCTD in patients and relatives.

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“…NGS analysis and post-analytic assessment resulted in confirmation of a clinical diagnosis in 41 patients. In another patient, two separate HCTD were uncovered (Riise et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Diagnostics of Hereditary Connective Tissue Disorders by Genetic Next-Generation Sequencing

Pope

Ratajska

Johnsen

et al. 2019

Genetic Testing and Molecular Biomarkers

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“…Currently, 14 pathogenic variants in exon 2 of COL2A1 have been identified in 165 affected members from 22 families ( Table 2). 31,32,33,34,35,36,37,38,39,40,41,42,43 All of the 14 were located in the coding region of exon 2. Of the 14, six were nonsense mutations, seven were frameshift mutations, and one was a missense mutation ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

A novel deep intronic COL2A1 mutation in a family with early‐onset high myopia/ocular‐only Stickler syndrome

Sun

Xiao

et al. 2020

Ophthalmic Physiologic Optic

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Citation information: Sun W, Xiao X, Li S, Jia X, & Zhang Q. A novel deep intronic COL2A1 mutation in a family with early-onset high myopia/ ocular-only Stickler syndrome. Ophthalmic Physiol Opt 2020; 40: 281-288. https://doi. AbstractPurpose: To identify the genetic defect causing early-onset high myopia (eoHM)/ ocular-only Stickler syndrome (ocular-STL) in a large Chinese family. Methods: Genomic DNA and clinical data from a four-generation family with eoHM/ocular-STL were collected. Whole-exome sequencing was performed on one affected member in initial screening. Linkage scan based on microsatellite markers was carried out initially from candidate loci associated with autosomal dominant eoHM and Stickler syndrome. Sanger sequencing was used to detect potential variants. The pathogenicity of candidate variants was evaluated using mini genes ex vivo. Results: Eight patients and five unaffected members in the family participated in the study, in which the patients had high myopia with other variable ocular phenotypes but without extraocular abnormalities. Whole exome sequencing did not detect any potential pathogenic variant in all genes known to associate with the disease. The eoHM/ocular-STL in the family was mapped to markers around COL2A1 by candidate loci linkage scan, with a maximum lod score of 3.31 for D12S1590 at θ = 0. A novel deep intronic variant, c.86-50C > G in intron 1 of COL2A1, was detected by Sanger sequencing and co-segregated with eoHM/ocular-STL in the family. Ex vivo splicing test using mini genes confirmed that the variant created a new splicing acceptor 49 bp before the canonical splicing site of exon 2, resulted in addition of 49 bp fragment in the transcript (from c.86-49 to c.86-1) and premature termination. Conclusions: Linkage study, bioinformatics prediction, and ex vivo transcript analysis suggest a novel deep intronic variant adjacent to 5-prime of exon 2 of COL2A1, affecting exon 2 splicing, as a potential cause of ocular-STL in a large family. To our knowledge, this is the first report of an intronic variant around exon 2 as a cause of ocular-STL while a series of variants in the coding region of exon 2, a dispensable alternative-splicing exon for extraocular tissues, in COL2A1 have been reported to cause Stickler syndrome-related ocular phenotype alone.

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“…Upon literature review, reports of cases with similar musculoskeletal abnormalities during the neonatal period had been made, including diffuse hypotonia, bilateral club foot, and dislocation of hips and knee in addition to cardiovascular findings. These patients were initially misdiagnosed with either Larsen syndrome or Beals syndrome based on their clinical presentation (Caza et al, 2016;Riise et al, 2018). LDS was later diagnosed based on genetic testing.…”

Section: Discussionmentioning

confidence: 99%

Connective Tissue Disorders: One of The Main Differential Diagnosis of Congenital Hypotonia

Srinivasan¹,

Infante²,

Gupta³

2020

FMCR

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Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder that has been associated with mutations involving the TGFBR1/2, SMAD2/3, and TGFB2/3 genes. It is characterized by aneurysms, arterial tortuosity, hypertelorism and bifid uvula. We present the case of a full-term infant born with significant hypotonia and congenital anomalies who was eventually diagnosed with LDS. Physical findings were significant for decreased muscle tone, redundant skin on nape of the neck, small chin, widely spaced nipples, and bilateral club feet. Due to the multiple anomalies noted above, genetics consultation was obtained. A chromosomal analysis with reflex to SNP microarray analysis was performed, showing a normal female 46,XX. Given the complex nature of the patient's presentation and normal initial genetics studies, Whole Exome Sequencing (WES) was ordered, revealing a heterozygous -likely De Novo, pathogenic variant in the TGFBFR1 gene (p.Glu239del), consistent with autosomal dominant LDS. Upon literature review, different cases of LDS associated with congenital hypotonia have been described. Nevertheless, medical attention was often sought for other clinical indications such as musculoskeletal and cardiac abnormalities, with some cases mislabeled as Larsen or Beals syndrome. We propose that connective tissue disorders should be included in the main differential diagnosis of congenital hypotonia.

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Clinical diagnosis of Larsen syndrome, Stickler syndrome and Loeys-Dietz syndrome in a 19-year old male: a case report

Cited by 12 publications

References 24 publications

Diagnostics of Hereditary Connective Tissue Disorders by Genetic Next-Generation Sequencing

Diagnostics of Hereditary Connective Tissue Disorders by Genetic Next-Generation Sequencing

A novel deep intronic COL2A1 mutation in a family with early‐onset high myopia/ocular‐only Stickler syndrome

Connective Tissue Disorders: One of The Main Differential Diagnosis of Congenital Hypotonia

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