Bridging the language gap - A call for the wider use of Human phenotype ontology by non-geneticist clinicians when requesting genomic tests

Tchuisseu-Kwangoua, Larissa Ange; Kamtchum‐Tatuene, Joseph; Tekendo‐Ngongang, Cedrik; Pengelly, Reuben J.; Self, James

doi:10.1016/j.ejmg.2022.104679

Cited by 3 publications

(4 citation statements)

References 10 publications

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“…Miscommunication of clinical phenotype between clinicians and clinical scientists can lead to diagnostic errors, such as failing to order the necessary test, or making errors during analysis and variant interpretation due to phenotypic terminologies being missing, imprecise, or misinterpreted [ 143 ]. For example, clinicians may apply terms to describe the patient’s current phenotype without consideration of modifying factors such as surgery i.e.…”

Section: Discussionmentioning

confidence: 99%

“…a presenting adult with PCG, who may have had several surgeries and now displays corectopia or develops cataracts or corneal decompensation, as opposed to the naïve (pre-intervention) congenital disease features. Providing more information on the patient’s medical presentation would aid the interpretation process and boost the probability of diagnosing the patient [ 143 ]. The proper use of HPO terminology will eliminate misinterpretations during the analysis, thereby improving diagnostics [ 143 ].…”

Section: Discussionmentioning

confidence: 99%

“…Providing more information on the patient’s medical presentation would aid the interpretation process and boost the probability of diagnosing the patient [ 143 ]. The proper use of HPO terminology will eliminate misinterpretations during the analysis, thereby improving diagnostics [ 143 ].…”

Section: Discussionmentioning

confidence: 99%

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Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

Al-Saei,

Malka,

Owen

et al. 2024

BMC Genomics

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Childhood glaucoma (CG) encompasses a heterogeneous group of genetic eye disorders that is responsible for approximately 5% of childhood blindness worldwide. Understanding the molecular aetiology is key to improving diagnosis, prognosis and unlocking the potential for optimising clinical management. In this study, we investigated 86 CG cases from 78 unrelated families of diverse ethnic backgrounds, recruited into the Genomics England 100,000 Genomes Project (GE100KGP) rare disease cohort, to improve the genetic diagnostic yield. Using the Genomics England/Genomic Medicine Centres (GE/GMC) diagnostic pipeline, 13 unrelated families were solved (13/78, 17%). Further interrogation using an expanded gene panel yielded a molecular diagnosis in 7 more unrelated families (7/78, 9%). This analysis effectively raises the total number of solved CG families in the GE100KGP to 26% (20/78 families). Twenty-five percent (5/20) of the solved families had primary congenital glaucoma (PCG), while 75% (15/20) had secondary CG; 53% of this group had non-acquired ocular anomalies (including iris hypoplasia, megalocornea, ectopia pupillae, retinal dystrophy, and refractive errors) and 47% had non-acquired systemic diseases such as cardiac abnormalities, hearing impairment, and developmental delay. CYP1B1 was the most frequently implicated gene, accounting for 55% (11/20) of the solved families. We identified two novel likely pathogenic variants in the TEK gene, in addition to one novel pathogenic copy number variant (CNV) in FOXC1. Variants that passed undetected in the GE100KGP diagnostic pipeline were likely due to limitations of the tiering process, the use of smaller gene panels during analysis, and the prioritisation of coding SNVs and indels over larger structural variants, CNVs, and non-coding variants.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

Al-Saei,

Malka,

Owen

et al. 2024

BMC Genomics

View full text Add to dashboard Cite

show abstract

“…Today, the wide availability of genetic tests continuously extends our understanding of genetic disorders, but it also carries the risk of a limited use of a phenotype-based approach [ 15 ]. Conversely, clinical geneticists can play a key role in unravelling elusive diagnoses and atypical presentations.…”

Section: Discussionmentioning

confidence: 99%

The Phenotype-Based Approach Can Solve Cold Cases: The Paradigm of Mosaic Mutations of the CREBBP Gene

Marchetti,

Milani,

Pisciotta

et al. 2024

Genes

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Rubinstein–Taybi syndrome (RTS) is a rare genetic disorder characterized by intellectual disability, facial dysmorphisms, and enlarged thumbs and halluces. Approximately 55% of RTS cases result from pathogenic variants in the CREBBP gene, with an additional 8% linked to the EP300 gene. Given the close relationship between these two genes and their involvement in epigenomic modulation, RTS is grouped into chromatinopathies. The extensive clinical heterogeneity observed in RTS, coupled with the growing number of disorders involving the epigenetic machinery, poses a challenge to a phenotype-based diagnostic approach for these conditions. Here, we describe the first case of a patient clinically diagnosed with RTS with a CREBBP truncating variant in mosaic form. We also review previously described cases of mosaicism in CREBBP and apply clinical diagnostic guidelines to these patients, confirming the good specificity of the consensus. Nonetheless, these reports raise questions about the potential underdiagnosis of milder cases of RTS. The application of a targeted phenotype-based approach, coupled with high-depth NGS, may enhance the diagnostic yield of whole-exome sequencing (WES) in mild and mosaic conditions.

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Current Management of Pediatric Nystagmus

Bradshaw,

Self,

Lee

2024

Advances in Ophthalmology and Optometry

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Bridging the language gap - A call for the wider use of Human phenotype ontology by non-geneticist clinicians when requesting genomic tests

Cited by 3 publications

References 10 publications

Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

Increasing the diagnostic yield of childhood glaucoma cases recruited into the 100,000 Genomes Project

The Phenotype-Based Approach Can Solve Cold Cases: The Paradigm of Mosaic Mutations of the CREBBP Gene

Current Management of Pediatric Nystagmus

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