ABCMdb

PMID: 25674778

Baker MW, Atkins AE, Cordovado SK, Hendrix M, Earley MC, Farrell PM
Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study.
Genet Med. 2015 Feb 12. doi: 10.1038/gim.2014.209., [PubMed]

Sentences

No. Mutations Sentence Comment

15 ABCC7 p.Gly551Asp ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly1244Glu ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Asn1303Lys ABCC7 p.Gly542* ABCC7 p.Arg1162* ABCC7 p.Ser1251Asn ABCC7 p.Arg352Gln ABCC7 p.Pro205Ser ABCC7 p.Leu206Trp ABCC7 p.Gln493* ABCC7 p.Val520Phe ABCC7 p.Gly85Glu ABCC7 p.Arg560Thr ABCC7 p.Pro67Leu ABCC7 p.Thr338Ile ABCC7 p.Leu1065Pro ABCC7 p.Arg1158* ABCC7 p.Met1101Lys ABCC7 p.Arg1066Cys ABCC7 p.Tyr1092* ABCC7 p.Tyr1092* ABCC7 p.Gln525* ABCC7 p.His199Tyr ABCC7 p.Ser945Leu ABCC7 p.Gln552* ABCC7 p.Trp401* ABCC7 p.Trp401* ABCC7 p.Lys710* ABCC7 p.Gly970Arg ABCC7 p.Gln98* ABCC7 p.Arg764* ABCC7 p.Arg117Cys ABCC7 p.Ser489* ABCC7 p.Gln890* ABCC7 p.Trp1089* ABCC7 p.Trp1204* ABCC7 p.Trp1204* ABCC7 p.Leu1077Pro ABCC7 p.Glu92Lys ABCC7 p.Trp846* ABCC7 p.Ser1196* ABCC7 p.Arg1066His ABCC7 p.Ile336Lys ABCC7 p.Arg851* ABCC7 p.Arg560Lys ABCC7 p.Ser492Phe ABCC7 p.Gly178Arg ABCC7 p.Asp110His ABCC7 p.Gly330* ABCC7 p.Ala559Thr ABCC7 p.Arg709* ABCC7 p.Glu822* ABCC7 p.Glu92* ABCC7 p.Glu1104* ABCC7 p.Gln1313* ABCC7 p.Leu732* ABCC7 p.Leu467Pro Correspondence: Mei W. Baker (mwbaker@wisc.edu) Improving newborn screening for cystic fibrosis using next-generation sequencing technology: a technical feasibility study Mei W. Baker, MD1,2 , Anne E. Atkins, MPH2 , Suzanne K. Cordovado, PhD3 , Miyono Hendrix, MS3 , Marie C. Earley, PhD3 and Philip M. Farrell, MD, PhD1,4 Table 1ߒ CF-causing or varying consequences mutations in the MiSeqDx IUO Cystic Fibrosis System c.1521_1523delCTT (F508del) c.2875delG (3007delG) c.54-5940_273ߙ+ߙ10250del21kb (CFTRdele2,3) c.3909C>G (N1303K) c.3752G>A (S1251N) Mutations that cause CF when combined with another CF-causing mutation c.1624G>T (G542X) c.2988ߙ+ߙ1G>A (3120ߙ+ߙ1G->A) c.3964-78_4242ߙ+ߙ577del (CFTRdele22,23) c.613C>T (P205S) c.1021T>C (S341P) c.948delT (1078delT) c.2988G>A (3120G->A) c.328G>C (D110H) c.200C>T (P67L) c.1397C>A (S466X(C>A)) c.1022_1023insTC (1154insTC) c.2989-1G>A (3121-1G->A) c.3310G>T (E1104X) c.3937C>T (Q1313X) c.1397C>G (S466X(C>G)) c.1081delT (1213delT) c.3140-26A>G (3272-26A->G) c.1753G>T (E585X) c.658C>T (Q220X) c.1466C>A (S489X) c.1116ߙ+ߙ1G>A (1248ߙ+ߙ1G->A) c.3528delC (3659delC) c.178G>T (E60X) c.115C>T (Q39X) c.1475C>T (S492F) c.1127_1128insA (1259insA) c.3659delC (3791delC) c.2464G>T (E822X) c.1477C>T (Q493X) c.1646G>A (S549N) c.1209ߙ+ߙ1G>A (1341ߙ+ߙ1G->A) c.3717ߙ+ߙ12191C>T (3849ߙ+ߙ10kbC->T) c.2491G>T (E831X) c.1573C>T (Q525X) c.1645A>C (S549R) c.1329_1330insAGAT (1461ins4) c.3744delA (3876delA) c.274G>A (E92K) c.1654C>T (Q552X) c.1647T>G (S549R) c.1393-1G>A (1525-1G->A) c.3773_3774insT (3905insT) c.274G>T (E92X) c.2668C>T (Q890X) c.2834C>T (S945L) c.1418delG (1548delG) c.262_263delTT (394delTT) c.3731G>A (G1244E) c.292C>T (Q98X) c.1013C>T (T338I) c.1545_1546delTA (1677delTA) c.3873ߙ+ߙ1G>A (4005ߙ+ߙ1G->A) c.532G>A (G178R) c.3196C>T (R1066C) c.1558G>T (V520F) c.1585-1G>A (1717-1G->A) c.3884_3885insT (4016insT) c.988G>T (G330X) c.3197G>A (R1066H) c.3266G>A (W1089X) c.1585-8G>A (1717-8G->A) c.273ߙ+ߙ1G>A (405ߙ+ߙ1G->A) c.1652G>A (G551D) c.3472C>T (R1158X) c.3611G>A (W1204X) c.1679ߙ+ߙ1.6kbA>G (1811ߙ+ߙ1.6kbA->G) c.274-1G>A (406-1G->A) c.254G>A (G85E) c.3484C>T (R1162X) c.3612G>A (W1204X) c.1680-1G>A (1812-1G->A) c.4077_4080delTGTTinsAA (4209TGTT->AA) c.2908G>C (G970R) c.349C>T (R117C) c.3846G>A (W1282X) c.1766ߙ+ߙ1G>A (1898ߙ+ߙ1G->A) c.4251delA (4382delA) c.595C>T (H199Y) c.1000C>T (R334W) c.1202G>A (W401X) c.1766ߙ+ߙ3A>G (1898ߙ+ߙ 3A->G) c.325_327delTATinsG (457TAT->G) c.1007T>A (I336K) c.1040G>A (R347H) c.1203G>A (W401X) c.2012delT (2143delT) c.442delA (574delA) c.1519_1521delATC (I507del) c.1040G>C (R347P) c.2537G>A (W846X) c.2051_2052delAAinsG (2183AA->G) c.489ߙ+ߙ1G>T (621ߙ+ߙ 1G->T) c.2128A>T (K710X) c.1055G>A (R352Q) c.3276C>A (Y1092X (C>A)) c.2052delA (2184delA) c.531delT (663delT) c.3194T>C (L1065P) c.1657C>T (R553X) c.3276C>G (Y1092X (C>G)) c.2052_2053insA (2184insA) c.579ߙ+ߙ1G>T (711ߙ+ߙ 1G->T) c.3230T>C (L1077P) c.1679G>A (R560K) c.366T>A (Y122X) c.2175_2176insA (2307insA) c.579ߙ+ߙ3A>G (711ߙ+ߙ 3A->G) c.617T>G (L206W) c.1679G>C (R560T) - c.2215delG (2347delG) c.579ߙ+ߙ5G>A (711ߙ+ߙ 5G->A) c.1400T>C (L467P) c.2125C>T (R709X) - c.2453delT (2585delT) c.580-1G>T (712-1G->T) c.2195T>G (L732X) c.223C>T (R75X) - c.2490ߙ+ߙ1G>A (2622ߙ+ߙ1G->A) c.720_741delAGGGAG AATGATGATGAAGTAC (852del22) c.2780T>C (L927P) c.2290C>T (R764X) - c.2583delT (2711delT) c.1364C>A (A455E) c.3302T>A (M1101K) c.2551C>T (R851X) - c.2657ߙ+ߙ5G>A (2789ߙ+ߙ5G->A) c.1675G>A (A559T) c.1A>G (M1V) c.3587C>G (S1196X) - Mutations/variants that were validated in this study are in bold. CF, cystic fibrosis. Table 1ߒ Continued on next page reduce carrier detection and potentially improve the positive predictive value (PPV), the NBS goals of equity and the highest possible sensitivity become more difficult to achieve. Login to comment 31 ABCC7 p.Arg117His ABCC7 p.Asp1270Asn ABCC7 p.Arg74Trp ABCC7 p.Arg1070Gln ABCC7 p.Asp1152His ABCC7 p.Tyr569Asp ABCC7 p.Phe1052Val ABCC7 p.Ile1234Val ABCC7 p.Leu558Ser ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg ABCC7 p.Ser977Phe ABCC7 p.Asp614Gly ABCC7 p.Asp579Gly ABCC7 p.Leu227Arg Both methods used 5 &#b5;l of isolated DNA for the NGS assay. NGS assay for detection of CFTR mutations/variants CFTR mutations are described using both the international nomenclature of the Human Genome Variation Society Mutations that have varying consequences c.3454G>C (D1152H) c.3154T>G (F1052V) c.3208C>T (R1070W) c.2930C>T (S977F) - c.3808G>A (D1270N) c.3205G>A (G1069R) c.350G>A (R117H) PolyTG/ polyT - c.1736A>G (D579G) c.3209G>A (R1070Q) c.220C>T (R74W) - - Mutations still under evaluation c.2657ߙ+ߙ2_2657ߙ+ߙ3insA (2789ߙ+ߙ2insA) c.680T>G (L227R) c.1705T>G (Y569D) - - c.1841A>G (D614G) c.1673T>C (L558S) - - - c.3700A>G (I1234V) c. Login to comment 32 ABCC7 p.Val754Met ABCC7 p.Arg75Gln ABCC7 p.Ser1235Arg ABCC7 p.Arg668Cys ABCC7 p.Gly576Ala ABCC7 p.Arg31Cys ABCC7 p.Leu997Phe ABCC7 p.Ile1027Thr ABCC7 p.Arg1162Leu ABCC7 p.Thr360Lys ABCC7 p.Gln359Lys [1075C>A;1079C>A] (Q359K/T360K) - - - Mutations that do not cause CF when combined with another CF-causing mutation c.1727G>C (G576A) c.3485G>T (R1162L) c.224G>A (R75Q) - - c.3080T>C (I1027T) c.91C>T (R31C) c.3705T>G (S1235R) - - c.2991G>C (L997F) c.2002C>T (R668C) c.2260G>A (V754M) - - Mutations/variants that were validated in this study are in bold. CF, cystic fibrosis. Table 1ߒContinued (http://www.hgvs.org/mutnomen/) and legacy mutation nomenclature (http://www.cftr2.org/browse.php). Login to comment 66 ABCC7 p.Asp1152His ABCC7 p.Asp1152His Of the four CFTR mutations with varying consequences, two cases with an F508del/D1152H genotype were labeled "carrier" based on the sweat test results and the initial clinical assessment, whereas another F508del/D1152H genotype was labeled as CRMS. Login to comment 67 ABCC7 p.Asp1152His Note that the D1152H mutation is associated with variable clinical consequences. Login to comment 74 ABCC7 p.Arg117His ABCC7 p.Arg347His ABCC7 p.Arg117Cys ABCC7 p.Asp110His ABCC7 p.Gln1313* ABCC7 p.Gln1313* However, the sensitivity of the IRT/NGS algorithm would have decreased as much as 50% for classic CF cases when a positive screen is defined as two CF-causing mutations because of uncommon mutations found in five patients Table 2ߒ Cases with a second mutation detected from the next-generation sequencing panel Case no. IRT (ng/ml) Second-tier DNA Additional mutation Sweat chloride (mmol/l) Clinical assessmenta Test 1 Test 2 1 64 F508del D110H 71.4 67.1 CF 2 327 F508del Q1313X N/A N/A CF 3 297 F508del Q1313X N/A N/A CF 4 71 R117H (7T) R347H 45.2 41.5 CRMSb 5 148 F508del R117C 40 38 CRMSb 6 66 F508del 5Tc 36.9 30.8 CRMSb 7 147 F508del D1152Hc 27.9 24.6 CRMSb 8 121 F508del D1152Hc 11 QNS Carrier 9 176 F508del D1152Hc 24 26 Carrier CF, cystic fibrosis; CRMS, CFTR-related metabolic syndrome; IRT, immunoreactive trypsinogen; QNS, quantity not sufficient. Login to comment 78 ABCC7 p.Asn1303Lys ABCC7 p.Gly480Asp Table 3ߒ Affected cases without the second mutation detected from the next-generation sequencing panel Case no. IRT (ng/ml) Second-tier DNA Sweat chloride (mmol/l) Clinical assessment Additional information Test 1 Test 2 1 237 F508del 134.1 Quantity not sufficient CF - 2 102 2789ߙ+ߙ5G>A 56.3 53.7 CRMS c.2909-15T>G identified by DNA sequencing 3 101 N1303K 79 75 CF No CFTR gene deletion was identified by Multiplex ligation-dependent probe amplification 4 144 F508del 100 87 CF G480D identified by DNA sequencing 5 58 F508del 55.2 55.1 CRMS - CF, cystic fibrosis; CRMS, CFTR-related metabolic syndrome; IRT, immunoreactive trypsinogen. Login to comment 84 ABCC7 p.Met1101Lys ABCC7 p.His199Tyr ABCC7 p.Ser492Phe In addition, CFTR panels being used have insufficient mutations to allow the detection of minority populations with uncommon CF-causing mutations that can cause inequities in NBS, such as M1101K (c.3302T>A), more commonly found in Hutterite populations,26 and H199Y (c.595C>T) and S492F (c.1475C>T), more commonly found in Hispanic populations. Login to comment 87 ABCC7 p.Gly551Asp Another shortcoming of currently used CFTR screening panels is that they also fail to detect class III mutations other than G551D (c.1652G>A) that can now be treated effectively by CFTR modulators.28,29 The overall goal of this project was to develop a strategy for improving equity and increasing the chance of identifying two CF-causing mutations in infants with CF through NBS. Login to comment 101 ABCC7 p.Tyr849* ABCC7 p.Gly1047Arg Because Wisconsin has genotype data on more than 500 patients with CF diagnosed through screening, we sought to understand how many CF cases have uncommon mutations not currently on the CFTR2 list; we found the five cases reported herein as well as other ones found previously, including G1047R, also referred to as 3139 G>C (c.3271G>C), Y849X (c.2679C>A), and 2043delG (c.2043delG). Login to comment