A universal carrier test for the long tail of Mendelian disease

Srinivasan, Balaji; Evans, E. Edward; Flannick, Jason; Patterson, Amy S.; Chang, Chris; Anh, Tuan Pham; Young, Sharon Neu; Kaushal, Amit; Lee, James; Jacobson, Jay A.; Patrizio, Pasquale

doi:10.1016/j.rbmo.2010.05.012

Cited by 91 publications

(48 citation statements)

References 82 publications

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“…Population-based carrier testing is not widely available, although several more common PAH-deficiency alleles are included in at least one of the emerging Universal Genetic Testing panels that are commercially available. 62 Genetic counseling is important to adequately inform couples of their residual risk.…”

Section: Carrier Testingmentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

540

443

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Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

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Section: Carrier Testingmentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

540

443

View full text Add to dashboard Cite

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“…The technological capability for multiplex carrier genetic screening continues to expand (Srinivasan et al 2010), and the potential to harness next-generation sequencing for carrier screening of more than a thousand severe recessive childhood conditions is becoming a reality as costs continue to decrease (Bell et al 2011). With the advent of direct-toconsumer genetic testing and the ability to perform these tests at home, it is increasingly important that decisions couples make about the utility of carrier genetic testing are supported by informed but non-directive health professionals who can provide medical follow-up, if necessary (Borry et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Carrier screening in preconception consultation in primary care

Metcalfe

2011

J Community Genet

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Discussing carrier screening during preconception consultation in primary care has a number of advantages in terms of promoting autonomy and enabling the greatest range of reproductive choices. For those with a family history of an inherited condition, this ought to be a routine discussion; however, this can be expanded to include the wider population, especially for those conditions for which carrier frequencies are considered relatively common. There is published literature from around the world regarding experiences with carrier screening in primary care for cystic fibrosis, haemoglobinopathies, fragile X syndrome, Tay-Sachs disease and spinal muscular atrophy, although many of these have tended to focus on consultations during rather than before pregnancy. Overall, these studies reveal that population carrier screening is well received by the participants with apparent minimal psychosocial harms; however, challenges exist in terms of approaches to ensure couples receive adequate information to make personally relevant decisions and for ongoing health professional engagement.

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“…7 FXS and cystic fibrosis studies consistently show a preference for carrier screening over other screening options, with this occurring ideally before pregnancy. [31][32][33] Increasingly, carrier screening for panels of genetic conditions are being offered 34 and a carrier screening program combining testing for SMA, FXS and cystic fibrosis has recently been launched in Victoria, Australia; uptake of testing has not yet been determined. As more conditions are added to carrier screening panels, it will be important to understand couple's decision-making, especially for conditions in which prognostic outcomes are not always clear.…”

Section: Description Of Participantsmentioning

confidence: 99%