The Role of De Novo Variants in Patients with Congenital Diaphragmatic Hernia

Bendixen, Charlotte; Reutter, Heiko

doi:10.3390/genes12091405

Cited by 7 publications

(4 citation statements)

References 71 publications

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“…None of the major reviews on this topic recognize this curious association. [17][18][19][20] Among the patients of cutis laxa, CDH has also been reported in ARCL-1A and ARCL-1B; but the frequency seldom exceeds 10%. [4] Thus, the high frequency of 57% makes CDH a characteristic clinical feature of URDS.…”

Section: Discussionmentioning

confidence: 99%

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On the curious association of diaphragmatic hernia and Urban-Rifkin-Davis Syndrome (Autosomal Recessive Cutis Laxa-1C): A collective review of 16 cases

Raveenthiran,

Darun,

Pavithra

et al. 2024

J Neonatal Surg

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Background: Autosomal recessive cutis laxa type-1C is also known as Urban-Rifkin-Davis syndrome (URDS). It is known to affect cardiopulmonary, integumentary, gastrointestinal, musculoskeletal and genitourinary systems. However, its frequent association with congenital diaphragmatic hernia has not previously been highlighted. Case Presentation: A newborn male with cutis laxa presented with respiratory distress at birth. The cause of dyspnoea was perinatal strangulation of the stomach in hiatus hernia. After surgical repair of the hernia, his respiratory distress temporarily improved but kept recurring periodically by various mechanisms in sequence namely pulmonary hypertension, tracheomalacia, pulmonary emphysema and finally he succumbed to pneumothorax. Genetic analysis revealed his skin condition as autosomal recessive cutis laxa type-1C which is also known as URDS. Exome sequencing revealed a novel frameshift mutation c.426delC (p.Cys143Alafs*41) of the LTBP4 gene in the exon 5 of Chromosome 19. Conclusion: Out of the 28 cases of URDS reported in the world literature 57% had congenital diaphragmatic hernia (CDH) and 53% of them died during infancy. Such a high incidence of CDH is not observed in other subtypes of elastic disorders. Thus, congenital diaphragmatic defects appear to be a characteristic diagnostic feature of URDS in patients with cutis laxa.

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Section: Discussionmentioning

confidence: 99%

“…In addition to LTBP-4 gene, more than 2 dozen genes such as FBN1, FBLN4 and FBLN5 also take part in normal elastogenesis. [19][20][21] We hypothesize that the nature of gene mutations might be responsible for site-specific elastic deficiency. This may explain the high frequency of CDH in URDS as compared to other varieties of CL.…”

Section: Discussionmentioning

confidence: 99%

On the curious association of diaphragmatic hernia and Urban-Rifkin-Davis Syndrome (Autosomal Recessive Cutis Laxa-1C): A collective review of 16 cases

Raveenthiran,

Darun,

Pavithra

et al. 2024

J Neonatal Surg

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“…Studies on de novo copy number variations (CNVs) have not yet shown an association between an excess of chromosome 9 and CDH. However, several genes, such as ABL1, TLN1, PLPP6, and NOTCH1 were reported to be associated with CDH as a de novo variant in chromosome 9 [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Severe Congenital Diaphragmatic Hernia With Trisomy 9: A Case Report and Review of the Literature

Fuma¹,

Kotani²,

Nakamura³

et al. 2022

Cureus

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Congenital diaphragmatic hernia (CDH) is known to be complicated with various chromosomal abnormalities. However, the grade of pulmonary hypoplasia of CDH complicated by trisomy 9 is not known. This information is essential to the mother who has had a fetus with the same complication. We report a case of severe CDH with trisomy 9. The fetus had fetal growth restriction and multiple anomalies, including severe left CDH (observed/expected lung-to-head ratio 13.7%, liver-up, stomach grade 3 in Kitano classification), mild ventriculomegaly, low-set ear, rocker bottom, and single umbilical artery. Chromosomal test by amniocentesis showed a karyotype of 47,XX,+9. The neonate was born alive at 34 weeks but died 49 minutes after birth. In the literature review, this case and seven cases of complete trisomy 9 had CDH, and four of them were explained as "large" or "severe" CDH. In conclusion, trisomy 9 might be occasionally complicated by severe CDH.

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“…Pathogenic genetic alterations-both in complex and in isolated CDH-are associated with a worse prognosis (33). Moreover, de novo pathogenic alterations are seen more often in complex CDH (34)(35)(36). Phenotypical complex patients could be more likely to receive a genetic test.…”

Section: Isolated Cdh and Complex Cdhmentioning

confidence: 99%

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge

et al. 2022

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Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck—largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic—and likely mechanistic—variability hampers individualpatient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

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The Role of De Novo Variants in Patients with Congenital Diaphragmatic Hernia

Cited by 7 publications

References 71 publications

On the curious association of diaphragmatic hernia and Urban-Rifkin-Davis Syndrome (Autosomal Recessive Cutis Laxa-1C): A collective review of 16 cases

On the curious association of diaphragmatic hernia and Urban-Rifkin-Davis Syndrome (Autosomal Recessive Cutis Laxa-1C): A collective review of 16 cases

Severe Congenital Diaphragmatic Hernia With Trisomy 9: A Case Report and Review of the Literature

Unraveling the Genetics of Congenital Diaphragmatic Hernia: An Ongoing Challenge

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