Ciliopathies: Coloring outside of the lines

Strong, Alanna; Liu, Dong; Mentch, Frank; Bedoukian, Emma; Hartung, Erum A.; Meyers, Kevin; Skraban, Cara; Wen, Jessica; Medne, Līvija; Glessner, Joseph; Watson, Deborah; Krantz, Ian D.; Hákonarson, Hákon

doi:10.1002/ajmg.a.62013

Cited by 8 publications

(5 citation statements)

References 28 publications

(29 reference statements)

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“…The p.Leu4239Arg variant was previously reported to be associated with Jeune syndrome [ 12 ]. Meanwhile, p.Ile2430Thr is located in the AAA3 nucleotide-binding pocket (amino acids 2251–2505) of the DYNC2H1 protein hexomeric ring-like ATP-hydrolysing motor domain ( , accessed on 2 March 2022) in close proximity with three known Jeune syndrome-associated variants, including p.Ser2423Tyr [ 16 ], described also as “pathogenic” in the ClinVar database ( , accessed on 2 March 2022), and p.Arg2426Cys [ 17 ] and p.Arg2426Leu [ 16 , 18 ]. Thus, taking into account the abovementioned facts, we consider both identified DYNC2H1 p.Ile2430Thr and p.Leu4239Arg variants as pathogenic and causative.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene—Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias

Stembalska

Rydzanicz

Kłaniewska

et al. 2022

Genes

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Skeletal dysplasias (SDs) are a large, heterogeneous group of mostly genetic disorders that affect the bones and cartilage, resulting in abnormal growth and development of skeletal structures. The high clinical and genetic diversity in SDs cause difficulties in prenatal diagnosis. To establish a correct prognosis and better management, it is very important to distinguish SDs with poor life-limiting prognosis or lethal SDs from other ones. Bad prognosis in foetuses is assessed on the basis of the size of the thorax, lung volumes, long bones’ length, bones’ echogenicity, bones’ angulation or presented fractures, and the concomitant presence of non-immune hydrops or visceral abnormalities. To confirm SD diagnosis and perform family genetic consultation, rapid molecular diagnostics are needed; therefore, the NGS method using a panel of genes corresponding to SD or whole-exome sequencing (WES) is commonly used. We report a case of a foetus showing long bones’ shortening and a narrow chest with short ribs, diagnosed prenatally with asphyxiating thoracic dystrophy, also known as Jeune syndrome (ATD; OMIM 208500), caused by compound heterozygous variants in the DYNC2H1 gene, identified by prenatally performed rapid-WES analysis. The missense variants in the DYNC2H1 gene were inherited from the mother (c.7289T>C; p.Ile2430Thr) and from the father (c.12716T>G; p.Leu4239Arg). The DYNC2H1 gene is one of at least 17 ATD-associated genes. This disorder belongs to the ninth group of SD, ciliopathies with major skeletal involvement. An extremely narrow, bell-shaped chest, and abnormalities of the kidneys, liver, and retinas were observed in most cases of ATD. Next to lethal and severe forms, clinically mild forms have also been reported. A diagnosis of ATD is important to establish the prognosis and management for the patient, as well as the recurrence risk for the family.

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Section: Discussionmentioning

confidence: 99%

Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene—Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias

Stembalska

Rydzanicz

Kłaniewska

et al. 2022

Genes

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“…SNVs and small indels were analyzed similarly as exome data with additional emphasis on regulatory variants by using the prediction scores by ANNOVAR. Further variant prioritization was performed with GDCross (Strong et al, 2021), which has incorporated ENCODE, GWAS, signaling pathways, and protein interactions to prioritize noncoding variants. Structural variations (SVs) were generated with three algorithms (Manta, Lumpy, and Wham) and annotated with SnpEff.…”

Section: Methodsmentioning

confidence: 99%

Genomic sequencing in a cohort of individuals with fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome

Matalon

Bhoj

et al. 2023

American J of Med Genetics Pt A

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Fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome (MIM 246570) is a rare disorder characterized by specific skeletal findings (fibular aplasia, shortened or bowed tibia, and oligosyndactyly of the foot and/or hand). Typically, no other anomalies, craniofacial dysmorphism, or developmental delays are associated.Here we report three unrelated individuals with limb anomalies consistent with FATCO syndrome who have been followed clinically for 5 years. Genetic testing of previously reported individuals with FATCO syndrome has not revealed a genetic diagnosis. However, no broader sequencing approaches have been reported. We describe the results of the three individuals with FATCO syndrome from exome and genome sequencing, all of which was nondiagnostic. Our study suggests that FATCO syndrome is not the result of a simple monogenic etiology.

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“…In one recent study, scientists did WGS on 4 children with suspected ciliopathies. (Strong et al 2021) The authors identified that all 4 children had mutations in cilia genes, but two patients had additional pathogenic variants for non-coding regions that are associated with liver disease.…”

Section: Is Whole-genome Sequencing More Robust At Diagnosing Ciliopa...mentioning

confidence: 99%

Cilia Disorders in the Genomics Era: Historical Overview and Commentary on Ciliopathy Diagnostics

Eskinazi

2023

SoS

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Introduction: Motile and sensory (primary) cilia are organelles that are found on the surface of almost all cells. Defects in cilia cause a number of multi-organ diseases known as ciliopathies, which have clinically heterogeneous symptoms. This heterogeneity makes diagnosing cilia disorders challenging and clinicians often rely on genetic sequencing to delineate ciliopathies from other diseases. However, there is not a consensus on which sequencing tools are most optimal for ciliopathy diagnosis and research. Methods: Here I review the implications of next-generation sequencing tools for ciliopathy diagnostics. I describe landmark studies that showed ciliopathies as genetic conditions and transition to the advantages and challenges of using next-generation sequencing techniques. In particular, I compare studies that utilized targeted sequencing with those that used whole-exome and/or whole-genome sequencing. Discussion: High throughput screens can identify novel cilia genes and show promise as a robust diagnostic tool in clinical settings. Moreover, I compare the effectiveness of whole-exome and whole-genome sequencing both for basic science research and clinical applications, arguing that whole-exome sequencing is a sufficient first pass in clinical settings. I also acknowledge that ciliopathies are associated with many, both significant and insignificant, genetic variants making interpreting next-generation sequencing data an ongoing challenge for scientists and clinicians. Conclusion: This review demonstrates the increasing body of knowledge on cilia genomics and highlights that next-generation sequencing will be integral towards optimizing diagnostics for these heterogeneous and debilitating group of disorders.

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Ciliopathies: Coloring outside of the lines

Cited by 8 publications

References 28 publications

Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene—Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias

Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene—Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias

Genomic sequencing in a cohort of individuals with fibular aplasia, tibial campomelia, and oligosyndactyly (FATCO) syndrome

Cilia Disorders in the Genomics Era: Historical Overview and Commentary on Ciliopathy Diagnostics

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