Trudy McKanna

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

INTRODUCTION: Chronic kidney disease (CKD) is a major public health issue in the USA. Identification of monogenic causes of CKD, which are present in ∼10% of adult cases, can impact prognosis and patient management. Broad gene panels can provide unbiased testing approaches, which are advantageous in phenotypically heterogeneous diseases. However, the use and yield of broad genetic panels by nephrologists in clinical practice is not yet well characterized. METHODS: Renal genetic testing, ordered exclusively for clinical purposes, predominantly by general and transplant nephrologists within the USA, was performed on 1,007 consecutive unique patient samples. Testing was performed using a commercially available next-generation sequencing-based 382 gene kidney disease panel. Pathogenic (P) and likely pathogenic (LP) variants were reported. Positive findings included a monoallelic P/LP variant in an autosomal dominant or X-linked gene and biallelic P/LP variants in autosomal recessive genes. RESULTS: Positive genetic findings were identified in 21.1% (212/1,007) of cases. A total of 220 positive results were identified across 48 genes. Positive results occurred most frequently in the PKD1 (34.1%), COL4A5 (10.9%), PKD2 (10.0%), COL4A4 (6.4%), COL4A3 (5.9%), and TTR (4.1%) genes. Variants identified in the remaining 42 genes comprised 28.6% of the total positive findings, including single positive results in 26 genes. Positive results in >1 gene were identified in 7.5% (16/212) of cases. CONCLUSIONS: Use of broad panel genetic testing by clinical nephrologists had a high success rate, similar to results obtained by academic centers specializing in genetics.

Rationale & ObjectiveThe identification of pathogenic variants in genes associated with chronic kidney disease can provide patients and nephrologists with actionable information to guide diagnoses and therapeutic plans. However, many nephrologists do not use genetic testing despite costs decreasing over time and more widespread availability.Study DesignWe conducted a survey to uncover the perceptions of general adult nephrologists about the utility of and barriers to genetic testing in clinical practice.Setting & ParticipantsThe online survey was administered to board-certified nephrologists (n = 10,054) in the United States.Analytical ApproachWe analyzed demographic characteristics of the survey respondents and their responses in the context of their use of genetic testing in routine clinical practice.ResultsA total of 149 nephrologists completed the survey, with 72% (107 of 149) reporting genetic test use in their practice. On average, tests were ordered for 3.8% of their patient population. Thirty-five percent of responses from nephrologists without a history of genetic test use ranked perceived barriers as “extremely significant” compared with 23% of responses from those who had previously used genetic tests. However, both users and nonusers of genetic tests indicated high cost (users: 46%, 49 of 107; nonusers 69%, 29 of 42) and poor availability or lack of ease (users: 33%, 35 of 107; nonusers: 57%; 24 of 42) of genetic testing as the most significant perceived barriers to implementation.LimitationsThe survey used in this study was not previously validated; additionally, because of the relatively small number of responses, there might have been a selection bias among the responders.ConclusionsAlthough most nephrologists reported using genetic tests in clinical practice, high costs and poor availability or the lack of ease of use were perceived as the most important barriers to routine adoption. These observations indicate that educational programs that cover a range of topics, from genetics of chronic kidney disease to selection of the test, may help mitigate these barriers and enhance the use of genetic testing in nephrology practice. The identification of pathogenic variants in genes associated with chronic kidney disease can provide patients and nephrologists with actionable information to guide diagnoses and therapeutic plans. However, many nephrologists do not use genetic testing despite costs decreasing over time and more widespread availability. We conducted a survey to uncover the perceptions of general adult nephrologists about the utility of and barriers to genetic testing in clinical practice. The online survey was administered to board-certified nephrologists (n = 10,054) in the United States. We analyzed demographic characteristics of the survey respondents and their responses in the context of their use of genetic testing in routine clinical practice. A total of 149 nephrologists completed the survey, with 72% (107 of 149) reporting genetic test use in their practice. On average, tests were ordered for 3.8% of their patient population. Thirty-five percent of responses from nephrologists without a history of genetic test use ranked perceived barriers as “extremely significant” compared with 23% of responses from those who had previously used genetic tests. However, both users and nonusers of genetic tests indicated high cost (users: 46%, 49 of 107; nonusers 69%, 29 of 42) and poor availability or lack of ease (users: 33%, 35 of 107; nonusers: 57%; 24 of 42) of genetic testing as the most significant perceived barriers to implementation. The survey used in this study was not previously validated; additionally, because of the relatively small number of responses, there might have been a selection bias among the responders. Although most nephrologists reported using genetic tests in clinical practice, high costs and poor availability or the lack of ease of use were perceived as the most important barriers to routine adoption. These observations indicate that educational programs that cover a range of topics, from genetics of chronic kidney disease to selection of the test, may help mitigate these barriers and enhance the use of genetic testing in nephrology practice.

OBJECTIVE: To identify pregnancies at increased risk for trisomy 13, trisomy 18 or triploidy attributable to low fetal fraction (FF). METHODS: A FF-based risk (FFBR) model was built using data from more than 165 000 singleton pregnancies referred for single-nucleotide polymorphism (SNP)-based non-invasive prenatal testing (NIPT). Based on maternal weight and gestational age (GA), FF distributions for normal, trisomy 13, trisomy 18 and triploid pregnancies were constructed and used to adjust prior risks for these abnormalities. A risk cut-off of ≥ 1% was chosen to define pregnancies at high risk for trisomy 13, trisomy 18 or triploidy (high FFBR score). The model was evaluated on an independent blinded set of pregnancies for which SNP-based NIPT did not return a result, and for which pregnancy outcome information was gathered retrospectively. RESULTS: The evaluation cohort comprised 1148 cases, of which approximately half received a high FFBR score. Compared with rates expected based on maternal age (MA) and GA, cases with a high FFBR score had a significantly increased rate of trisomy 13, trisomy 18 or triploidy combined (5.7% vs 0.7%; P < 0.001) and also of unexplained pregnancy loss (14.7% vs 10.4%; P < 0.001). For cases that did not receive a high FFBR score, the incidence of a chromosomal abnormality or pregnancy loss was not significantly different from that expected based on MA and GA. In this study cohort, the sensitivity of the FFBR model for detection of trisomy 13, trisomy 18 or triploidy was 91.4% (95% CI, 76.9-98.2%) with a positive predictive value of 5.7% (32/564; 95% CI, 3.9-7.9%). CONCLUSIONS: For pregnancies with a FF too low to receive a result on standard NIPT, the FFBR algorithm identified a subset of cases at increased risk for trisomy 13, trisomy 18 or triploidy. For the remainder of cases, the risk of a fetal chromosomal abnormality was unchanged from that expected based on MA and GA. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.