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1.
Aust J Gen Pract ; 48(3): 106-110, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31256466

RESUMO

BACKGROUND: General practitioners (GPs) provide advice to women and couples before and during pregnancy to optimise the health and wellbeing of couples and their child. Genetic carrier screening can identify the chance of couples having children with recessively inherited genetic conditions. The 2018 federal budget announced Mackenzie's Mission, a $20 million Medical Research Future Fund project investigating how such screening could be offered to all couples who wish to access it. OBJECTIVE: The aim of this paper is to discuss historical and current screening methodologies, options for individuals and couples identified as having a high chance of having a child with a genetic condition, screening guidelines, Mackenzie's Mission and the implications of carrier screening in general practice. DISCUSSION: GPs are crucial to any population-wide genetic carrier screening program and are often the first health professional that women and couples see for preconception and early pregnancy care. Knowledge of genetic screening will be increasingly important as such programs are developed.

2.
Am J Med Genet A ; 179(8): 1585-1590, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175705

RESUMO

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain-of-function mutations in the regulatory (SUR2) and pore-forming (Kir6.1) subunits of KATP channels, respectively, suggesting that channel-blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg-1 kg-1 day-1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg-1 kg-1 day-1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.

3.
Hum Mutat ; 40(10): 1813-1825, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31215115

RESUMO

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

4.
J Med Genet ; 56(9): 629-638, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129566

RESUMO

BACKGROUND: Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. METHODS: Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. RESULTS: Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. CONCLUSION: These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes.

5.
Eur J Med Genet ; 62(5): 397-404, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31085343

RESUMO

Personal genome screening (PGenS) is increasingly being offered as a screen for future health management, and to identify carrier status pertinent to reproductive decision-making. The aim of this study was therefore to explore the experience of individuals who undertook PGenS through the 2014 Sydney "Understand Your Genome (UYG)" event and a 2015 offer of PGenS by Australian biotechnology company Life Letters (LL). Eligible individuals were invited to participate by their clinical geneticist (UYG), or email from Director of LL. Semi-structured telephone interviews with 17 individuals were audio-recorded, transcribed, de-identified and analyzed by two coders using thematic analysis with an inductive approach. Nine participants had genetic/genomics expertise and eight were well-informed health and business professionals. Individual participant PGenS results included: an autosomal dominant condition not previously clinically identified (n = 1); carrier status for recessive condition(s) (n = 8); a number of disease-causing variants associated with an increased susceptibility to an inherited disorder (n = 7); variants of uncertain significance (n = 5); and a few pharmacogenomically-relevant variants (n = 4). The majority of participants described the importance of pre-test genetic counseling, information and/or consent (n = 12). Some barriers to uptake were identified, including scepticism by GPs (n = 6), colleagues (n = 3), and family members (n = 2), as well as privacy concerns (n = 4). Those without genetic/genomics expertise were mostly motivated to have testing by curiosity or interest in personal health (6/8), one seeking a diagnosis for an inherited medical condition and another for future health management. For many with genetic/genomics experience, the motivation was professional interest (8/9) and/or curiosity (5/9), without concern for personal health risk (4/9). On reflection, despite this initial motivation by the latter, the test result had unanticipated personal impact for some of this group, which changed over time (4/5). Several later recognized this, as health problems developed or family history was interrogated more closely. For all participants, disclosure of results to extended family members was limited. Most participants felt personal and family implications and communication (5/17) and/or expectations (3/17) should be addressed at the pre-test session, including more emphasis on residual risk and changes in interpretation with developing phenotypes. Those without genetics/genomics expertise highlighted the need for easy to understand pre-test information and/or an example report to be provided (7/8). These results are consistent with a need to develop more accessible resources, and more personalized counseling approaches to address expectations, dissemination of results, and preparedness for unexpected findings.


Assuntos
Triagem e Testes Direto ao Consumidor/métodos , Testes Genéticos/métodos , Competência em Informação , Adulto , Atitude , Triagem e Testes Direto ao Consumidor/psicologia , Triagem e Testes Direto ao Consumidor/normas , Feminino , Testes Genéticos/normas , Humanos , Masculino , Pessoa de Meia-Idade
6.
J Genet Couns ; 28(2): 240-250, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30964588

RESUMO

The study aimed to explore with consanguineous couples in Australia the acceptability and perceived utility of whole exome reproductive carrier screening for autosomal recessive and X-linked recessive conditions. Semi-structured interviews with 21 consanguineous couples were conducted prior to the offer of screening. Interviews were coded, and thematic analysis was informed by an inductive approach. Three major themes were identified: experiences and attitudes of Australian consanguineous couples, childhood genetic conditions and beliefs, and the perceived utility of genomic screening. All but one couple had previously sought genetic advice, and a large majority of couples were aware of childhood conditions within their family or community. Thirteen couples perceived consanguinity as increasing the risk of having affected children. Nine spoke of premarital screening programs routinely conducted in their countries of origin. All supported the concept and availability of genomic reproductive carrier screening. Hypothetically, if found to be carriers of a severe childhood disorder, 13 couples reported they would test a pregnancy, and 12 of whom would consider termination of pregnancy or pre-implantation genetic diagnosis. Four couples would not test a pregnancy and two were unsure. A majority of couples would communicate potential at-risk status to family members, although there were some caveats. Fourteen couples chose to have exome screening and reported that they would utilize the results with the goal of preventing childhood conditions. Of these couples, nine (64%) had an affected child but were aware that testing may reveal they were at risk for a child with a different condition and five (71%) without an affected child. While from diverse ethnic and backgrounds, all couples practiced a religion and all but one couple were recruited from the same clinical genetics unit, with a likely higher genetic literacy and bias towards accepting genetic testing. However, the choice made by all couples was reportedly made with consideration of their personal values, their current family situation, and exome testing issues, including fear of incidental findings and concerns about test reliability.

8.
Am J Hum Genet ; 104(3): 542-552, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827498

RESUMO

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

9.
Medicine (Baltimore) ; 98(8): e14524, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813157

RESUMO

RATIONALE: Trio family-based whole exome sequencing (WES) is a powerful tool in the diagnosis of rare neurodevelopmental diseases, even in patients with the unclear diagnosis. There have been previous reports of variants in the phosphatidylinositol glycan anchor biosynthesis class T (PIGT) gene associated with multiple congenital anomalies, with a total of 14 affected individuals across 8 families. PATIENT CONCERNS: An 18-month-old boy of Greek ancestry presented with global developmental delay, generalized tonic-clonic seizures, hypotonia, renal cysts, esotropia, bilateral undescended testes, bilateral vesicoureteric reflux, marked cardiac dextroposition, bilateral talipes equinovarus, and dysmorphic features. DIAGNOSIS: WES revealed 2 compound heterozygous variants in the PIGT gene, c.[494-2A>G]; [547A>C]/p.[Asp122Glyfs*35]; [Thr183Pro]. The splicing mutation was demonstrated to lead to the skipping of exon 4. INTERVENTIONS: Seizures, infections, and other main symptoms were treated. OUTCOMES: The patient died at 2 years of age before the molecular diagnosis was achieved. Genetic counseling has been offered to the family. LESSONS: Most of the clinical features of the patient are in agreement with the previously described PIGT cases corroborating the usefulness of WES as a diagnostic tool.


Assuntos
Anormalidades Múltiplas/genética , Aciltransferases/genética , Técnicas de Cultura de Células , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Evolução Fatal , Humanos , Lactente , Masculino , Hipotonia Muscular/genética , Mutação , Reação em Cadeia da Polimerase em Tempo Real , Convulsões/genética , Síndrome , Sequenciamento Completo do Exoma/métodos
10.
Cell Rep ; 25(10): 2729-2741.e6, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30517861

RESUMO

The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development.

11.
Genet Med ; 2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30293987

RESUMO

PURPOSE: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients. METHODS: Ninety-seven families with probands born with CHD requiring surgical correction were recruited for genome sequencing. At minimum, a proband-parents trio was sequenced per family. GS data were analyzed via a two-tiered method: application of a high-confidence gene screen (hcCHD), and comprehensive analysis. Identified variants were assessed for pathogenicity using the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. RESULTS: Clinically relevant genetic variants in known and emerging CHD genes were identified. The hcCHD screen identified a clinically actionable variant in 22% of families. Subsequent comprehensive analysis identified a clinically actionable variant in an additional 9% of families in genes with recent disease associations. Overall, this two-tiered approach provided a clinically relevant variant for 31% of families. CONCLUSIONS: Interrogating GS data using our two-tiered method allowed identification of variants with high clinical utility in a third of our heterogeneous cohort. However, association of emerging genes with CHD etiology, and development of novel technologies for variant assessment and interpretation, will increase diagnostic yield during future reassessment of our GS data.

13.
J Genet Couns ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30187264

RESUMO

The study aimed to explore with consanguineous couples in Australia the acceptability and perceived utility of whole exome reproductive carrier screening for autosomal recessive and X-linked recessive conditions. Semi-structured interviews with 21 consanguineous couples were conducted prior to the offer of screening. Interviews were coded, and thematic analysis was informed by an inductive approach. Three major themes were identified: experiences and attitudes of Australian consanguineous couples, childhood genetic conditions and beliefs, and the perceived utility of genomic screening. All but one couple had previously sought genetic advice, and a large majority of couples were aware of childhood conditions within their family or community. Thirteen couples perceived consanguinity as increasing the risk of having affected children. Nine spoke of premarital screening programs routinely conducted in their countries of origin. All supported the concept and availability of genomic reproductive carrier screening. Hypothetically, if found to be carriers of a severe childhood disorder, 13 couples reported they would test a pregnancy, and 12 of whom would consider termination of pregnancy or pre-implantation genetic diagnosis. Four couples would not test a pregnancy and two were unsure. A majority of couples would communicate potential at-risk status to family members, although there were some caveats. Fourteen couples chose to have exome screening and reported that they would utilize the results with the goal of preventing childhood conditions. Of these couples, nine (64%) had an affected child but were aware that testing may reveal they were at risk for a child with a different condition and five (71%) without an affected child. While from diverse ethnic and backgrounds, all couples practiced a religion and all but one couple were recruited from the same clinical genetics unit, with a likely higher genetic literacy and bias towards accepting genetic testing. However, the choice made by all couples was reportedly made with consideration of their personal values, their current family situation, and exome testing issues, including fear of incidental findings and concerns about test reliability.

14.
Genet Med ; 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29961766

RESUMO

PURPOSE: To provide proof of concept by broadening preconception screening beyond targeted testing to inform reproductive risk in consanguineous couples. METHODS: Consanguineous couples were screened for autosomal recessive and X-linked disorders using the TruSight One panel of 4,813 genes associated with human disease. RESULTS: We recruited 22 couples, of whom 15 elected to have sequencing. We found four couples to be at risk of autosomal recessive disorders, including one with a child affected by Poretti-Boltshauser syndrome (a diagnosis not made prior to the study) and another previously known to carry a ß-globin variant. Two couples were found to carry variants unrelated to known family history. These variants were in the genes C5orf42 (associated with Joubert syndrome and orofaciodigital syndrome) and GYS2 (associated with glycogen synthase deficiency). One known variant was not detected-a single exon deletion in FAM20C. We would not expect to identify this variant with the methodology employed. Of the four variants identified, only the ß-globin variant would have been found using available commercial preconception screening panels. CONCLUSION: Preconception screening of consanguineous couples for recessive and X-linked disorders using genomic sequencing is practicable, and is likely to detect many more at-risk couples than any targeted panel could achieve. A couples-based approach greatly reduces the associated analysis and counselling burden.

15.
Am Heart J ; 201: 33-39, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29910053

RESUMO

BACKGROUND: Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information. METHODS: A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses. RESULTS: A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with "neurotransmitters," "axon guidance," and those incorporating "RASopathy" genes in the development of NDD in CHD patients. CONCLUSIONS: These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group.

16.
Genet Med ; 20(11): 1387-1395, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29493584

RESUMO

PURPOSE: As the molecular basis of congenital heart disease (CHD) comes into sharper focus, cardiac genetics services are likely to play an increasingly important role. This study aimed to identify parents' preferences for, and willingness to participate in, clinical genetics services for CHD. METHODS: A discrete choice experiment was developed to assess parents' preferences for pediatric cardiogenetics services based on four attributes: appointment format, health professionals involved, waiting time, and information format. Data were analyzed using a mixed logit model. RESULTS: One hundred parents with a living child diagnosed with CHD requiring surgical intervention between 2000 and 2009 completed the discrete choice experiment. Parents expressed a clear preference for cardiac genetics services featuring (i) a single appointment, (ii) the presence of a clinical geneticist and a genetic counselor, (iii) both verbal (oral) and Web-based information about CHD and genetics, and (iv) availability of an appointment within 2 weeks. If offered such conditions, 93% of respondents indicated that they would attend. The choice of service was most strongly influenced by the presence of both a clinical geneticist and a genetic counselor. CONCLUSION: Parents of children with CHD favor a single, timely genetics appointment with both a geneticist and a genetic counselor present. If appointments offered match these preferences, uptake is likely to be high.

17.
Genet Med ; 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29595814

RESUMO

PurposeWhole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.MethodsWES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).ResultsReanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.ConclusionEarly application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.GENETICS in MEDICINE advance online publication, 29 March 2018; doi:10.1038/gim.2018.39.

18.
Front Cell Neurosci ; 12: 57, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593499

RESUMO

Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor-MOB2-in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of Mob2 within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development.

19.
Cell ; 172(5): 924-936.e11, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474920

RESUMO

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

20.
Mol Genet Genomic Med ; 6(2): 186-199, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29314763

RESUMO

BACKGROUND: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways. METHODS: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing. Sensitivity analysis was included with a range of commercial exome and multigene panels. RESULTS: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported. CONCLUSION: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.


Assuntos
Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Criança , Pré-Escolar , Análise Custo-Benefício/métodos , Exoma , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Doenças do Sistema Nervoso/genética , Estudos Retrospectivos , Análise de Sequência de DNA/economia , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Exoma/economia , Sequenciamento Completo do Exoma/métodos
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