Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Disease-causing mutation or benign alteration?

Hentschel, Julia; Riesener, G; Nelle, Heike; Stuhrmann, Manfred; Schöner, Anja; Sommerburg, Olaf; Fritzsching, Eva; Mall, Marcus; Eggeling, Ferdinand von; Mainz, Jochen G.

doi:10.1007/s00431-012-1672-1

Cited by 4 publications

(3 citation statements)

References 12 publications

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“…This amino acidic substitution in M6 domain of CFTR protein is nonconservative: methionine is replaced by lysine. This mutation was previously identified: (a) as innocuous polymorphism in a cystic fibrosis at-risk family [ 7 ]; (b) in compound heterozygosis with L346P in a Cypriot male individual [ 8 ]; and (c) in homozygote boy with respiratory symptoms and failure to thrive [ 9 ]. As reported by Hentschel et al [ 9 ], clinical relevance of p.M348K mutation remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…This mutation was previously identified: (a) as innocuous polymorphism in a cystic fibrosis at-risk family [ 7 ]; (b) in compound heterozygosis with L346P in a Cypriot male individual [ 8 ]; and (c) in homozygote boy with respiratory symptoms and failure to thrive [ 9 ]. As reported by Hentschel et al [ 9 ], clinical relevance of p.M348K mutation remains unclear. In this regard, the clinical and functional translation of CFTR (CFTR2) project represents a novel approach for clinical and functional annotation of mutations identified in disease-causing genes [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

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Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis

Molinario

Palumbo

Concolino

et al. 2015

Case Reports in Genetics

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Cystic fibrosis (CF; OMIM number 219700) is an autosomal recessive disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which results in abnormal viscous mucoid secretions in multiple organs and whose main clinical features are pancreatic insufficiency, chronic endobronchial infection, and male infertility. We report the case of a 47-year-old apparently normal male resulting in homozygosity for the mutation p.M348K from nonconsanguineous parents. The proband was screened using a standard panel of 70 different tested on NanoChip 400 platform. The massive parallel pyrosequencing on 454 JS machine allowed the second level analysis. The patient was firstly screened with two different platforms available in our laboratory, obtaining an ambiguous signal for the p.R347P mutation. For this reason we decided to clarify the discordant result of CFTR status by Next Generation Sequencing (NGS) using 454 Junior instrument. The patient is resulted no carrier of the p.R347P mutation, but NGS highlighted a homozygous substitution from T>A at position 1043 in the coding region, causing an amino acid substitution from methionine to lysine (p.M348K). Casual finding of p.M348K homozygote mutation in an individual, without any feature of classical or nonclassical CF form, allowed us to confirm that p.M348K is a benign rare polymorphism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis

Molinario

Palumbo

Concolino

et al. 2015

Case Reports in Genetics

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“…The G-BA protocol showed with [5,6]] und zur klinischen Evaluation überwiesen. Konnte eine CF nicht eindeutig diagnostiziert oder ausgeschlossen werden, erfolgte eine erweiterte Mutationsanalytik und/oder die Untersuchung der CFTR-vermittelten Chloridsekretion durch Kurzschlussstrommessung am Rektumschleimhautbiopsat [7,8,10].…”

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Neugeborenenscreening auf Mukoviszidose in Deutschland: Vergleich des neuen Screening-Protokolls mit einem Alternativprotokoll

et al. 2017

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Zusammenfassung Hintergrund Zur Einf?hrung des Neugeborenenscreening auf Mukoviszidose (CF) in Deutschland hat der Gemeinsame Bundesausschuss (G-BA) ein neues Screeningprotokoll mit der Bestimmung von Immunreaktiven Trypsinogen (IRT) als ersten und Pankreatitis assoziierten Protein (PAP) als zweiten Schritt eingef?hrt. In einem dritten Schritt folgt eine Analytik von 31 CFTR-Mutationen, um den positiven Vorhersagewert (PPV) gegen?ber einem rein biochemischen IRT/PAP-Protokoll zu erh?hen. Methoden Der Datenpool (n=372?906) einer Studie zur Evaluation eines rein biochemischen IRT/PAP-Protokolls wurde f?r den Vergleich des vom G-BA beschlossenen Protokolls mit einem von den Autoren vorgeschlagenen Alternativprotokoll genutzt. Der Unterschied beider Protokolle liegt im weiteren Vorgehen, wenn das IRT>99,9. Perzentile liegt. Im G-BA-Protokoll wird dann sowohl der PAP- als auch der DNA-Schritt, im Alternativprotokoll nur der PAP-Schritt umgangen. Ergebnisse Beide 3-stufigen Protokolle verlieren durch die DNA-Analytik im Vergleich zum 2-stufigen IRT/PAP-Protokoll nicht an Sensitivit?t. Unterschiede zeigten sich jedoch im PPV: Das G-BA-Protokoll zeigt mit 351 deutlich mehr falsch-positiv getestete Neugeborene (PPV 20,2%) als das Alternativprotokoll mit 31 (PPV 69,6%). Schlussfolgerung Das G-BA-Protokoll hat im Vergleich zum Alternativprotokoll die schlechtere Performance. Durch die zu erwartende h?here Zahl an falsch-positiv detektierten Neugeborenen im G-BA-Protokoll werden mehr Vorstellungen zur Konfirmationsdiagnostik und f?r Schwei?tests notwendig, mehr Familien verunsichert und h?here Kosten nach dem Screening verursacht.

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Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations

Sommerburg

Krulišová

Hammermann

et al. 2014

Journal of Cystic Fibrosis

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Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Disease-causing mutation or benign alteration?

Abstract: We assume that the homozygous alteration M348K is a harmless variant rather than a CF-causing mutation.

Cited by 4 publications

References 12 publications

Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis

Incidental Finding of a Homozygous p.M348K Asymptomatic Italian Patient Confirms the Many Faces of Cystic Fibrosis

Neugeborenenscreening auf Mukoviszidose in Deutschland: Vergleich des neuen Screening-Protokolls mit einem Alternativprotokoll

Comparison of different IRT-PAP protocols to screen newborns for cystic fibrosis in three central European populations

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