Newborn Screening for Cystic Fibrosis
in California
Martin Kharrazi, PhD, MPHa, Juan Yang, PhD, MSa, Tracey Bishop, BSa, Shellye Lessing, MSa, Suzanne Young, MPHb,
Steven Graham, MPHa,b, Michelle Pearl, PhDb, Helen Chow, PhDa, Thomson Ho, PhDa, Robert Currier, PhDa, Leslie Gaffneya,
Lisa Feuchtbaum, DrPHa, on behalf of the California Cystic Fibrosis Newborn Screening Consortium
abstract
OBJECTIVES: This article describes the methods used and the program performance results for the
first 5 years of newborn screening for cystic fibrosis (CF) in California.
METHODS: From July 16, 2007, to June 30, 2012, a total of 2 573 293 newborns were screened for CF
by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot
specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator
(CFTR) mutations in specimens with immunoreactive trypsinogen values $62 ng/mL (top 1.6%);
and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants
with $2 mutations/variants were referred to CF care centers for diagnostic evaluation and
follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone
genetic counseling.
RESULTS: Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers
were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially
assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after
age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive
predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations
were identified, including 78 novel variants. The median age at referral to a CF care center was
34 days (18 and 37 days for step 2 and 3 screening test–positive infants, respectively).
CONCLUSIONS:
The 3-step model had high detection and low false-positive levels in this diverse
population.
WHAT’S KNOWN ON THIS SUBJECT: Several
newborn screening models for cystic fibrosis
(CF) exist, including DNA-based models that use
mutation panels. There is limited experience with
models (such as used in California) that include
comprehensive DNA sequence testing methods
as part of newborn screening.
WHAT THIS STUDY ADDS: California’s 3-step
newborn screening model for CF showed high
efficiency, sensitivity, and positive predictive
value. More than 300 mutations were found,
reflecting the state’s diverse population. Some CF
transmembrane conductance regulator–related
metabolic syndrome cases converted to CF over
time.
a
California Department of Public Health, Richmond, California; and bSequoia Foundation, La Jolla, California
Dr Kharrazi conceptualized and designed the study and drafted the initial manuscript; Dr Yang
assisted with data collection at the cystic fibrosis specialty care centers (CFCs), analyzed and interpreted
the data, and reviewed and revised the manuscript; Ms Bishop helped design the data collection
instruments, helped coordinate data collection at the CFCs, and critically reviewed the manuscript;
Ms Lessing conceptualized and designed the cystic fibrosis carrier genetic counseling aspect of the study,
coordinated data collection of genetic counseling information, and critically reviewed the manuscript;
Ms Young helped design the data collection instruments, helped coordinate data collection at the CFCs,
helped analyze and interpret the data, and critically reviewed the manuscript; Mr Graham helped design
the 3-step algorithm and the data collection instruments, linked screen-positive cases to death record data,
helped analyze and interpret the data, and critically reviewed the manuscript; Dr Pearl helped design the
3-step algorithm and the data collection instruments and critically reviewed and revised the manuscript;
Dr Chow assisted in the development of cystic fibrosis laboratory testing, reviewed laboratory results, and
critically reviewed the manuscript; Dr Ho supervised screening laboratory data collection and critically
reviewed and revised the manuscript; Dr Currier assisted with analysis and interpretation of the data
and critically reviewed the manuscript; Ms Gaffney oversaw the design of the data collection instruments
and the study, and critically reviewed the manuscript; Dr Feuchtbaum assisted with analysis and
interpretation of the data and critically reviewed and revised the manuscript; and all authors approved the
final manuscript as submitted and agree to be accountable for all aspects of the work.
www.pediatrics.org/cgi/doi/10.1542/peds.2015-0811
DOI: 10.1542/peds.2015-0811
Accepted for publication Sep 2, 2015
ARTICLE
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PEDIATRICS Volume 136, number 6, December 2015
Cystic fibrosis (CF) is the most
common life-limiting autosomal
recessively inherited disease in white
populations.1 It is caused by
mutations in the cystic fibrosis
transmembrane conductance
regulator (CFTR) gene that encodes
the CFTR protein, which participates
in fluid homeostasis across mucosal
surfaces.2 In 2004, the Centers for
Disease Control and Prevention
concluded that newborn screening
(NBS) for CF was justified to
minimize the impact of nutritional
deficiencies and poor growth (and
possibly lung disease) caused by CF
through early detection and proper
care.3 By 2010, NBS for CF had been
instituted throughout the United
States.4
During development of NBS for CF
in California (2000–2005), the
California Department of Public
Health Genetic Disease Screening
Program (GDSP) established 6
requirements and goals (Fig 1). One
challenge that California faced was a
poor understanding of common CFTR
mutations within its large and
heterogeneous population. After
establishing a CF registry and
researching the CFTR mutations and
immunoreactive trypsinogen (IRT)
levels in CF case subjects and control
subjects from 3 main race/ethnic
groups in California, GDSP developed
a 3-step model (IRT–mutation
panel–DNA sequencing) for CF NBS.
The goal of this article is to present
the methods used and program
performance results for the first
5 years of routine CF NBS in California
after 2 to 7 years (average: 4.5 years)
FIGURE 1
Requirements and goals for the California CF
NBS program, 2005. CFC, cystic fibrosis specialty care Center; SCT, sweat chloride test.
PEDIATRICS Volume 136, number 6, December 2015
of follow-up. We discuss how well
the California model met its goals and
the implications of the findings on
our current understanding of CF
and cystic fibrosis transmembrane
conductance regulator–related
metabolic syndrome (CRMS)5 and on
other commonly used CF NBS models.
METHODS
The study population included infants
who underwent CF NBS in California
from July 16, 2007, to June 30,
2012. The CF algorithm (Fig 2) uses
the base program’s 1-time collection
on filter paper of blood spots through
a heel stick at $12 hours of age
(median: 30 hours). The filter paper
card is transported to 1 of 7
laboratories for analysis of serum IRT
by using the AutoDELFIA Neonatal
IRT Kit (PerkinElmer, Waltham, MA).
Quality control samples are
incorporated into each assay batch on
every analytical instrument used in
CF screening. Daily quality control
results are charted and examined for
short- and long-term drift. Specimens
with an IRT level $62 ng/mL (top
1.6%) are sent for analysis at the
Stanford Molecular Pathology
Laboratory (Stanford University, Palo
Alto, CA) using a 28- to 40-CFTR
mutation panel (Table 1). The IRT
cutoff was determined by maximizing
the sum of sensitivity and specificity
in a California study of archived
blood spots from 715 prescreening
CF case subjects and 5026 control
subjects. Mutations on the California
panel were selected accordingly: (1)
highest allelic frequencies from a
second study of 1648 comprehensively
genotyped, prescreening, California
CF cases to achieve a race/ethnicityspecific rate $95% of CF case
detection through mutation panel
testing in Hispanic, non-Hispanic white,
and African-American subjects; (2)
include 1 prevalent gross deletion not
detectable by using DNA sequence
testing, CFTRdele2,3(21kb)6; and
(3) include only mutations with clear
CF-causing potential. For example, the
common yet variable R117H
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mutation was not included on the
panel.7 After testing, IRT levels and
mutation panel results (when IRT is
positive) are reported at the same
time as analyte results for other
screened disorders. Newborns with
2 mutations identified after panel
testing are referred to 1 of 17
California- and Cystic Fibrosis
Foundation (CFF)-approved pediatric
cystic fibrosis specialty care center
(CFCs) for diagnostic evaluation and
follow-up.
Specimens found to have only
1 mutation after panel testing are sent
for either CFTR gene scanning and
sequence analysis using the Ambry
Test: CF (Ambry Genetics, Aliso Viejo,
CA)8,9 from July 16, 2007 to June 30,
2010 or direct CFTR DNA Sanger
sequencing at Stanford Molecular
Pathology Laboratory from July 1,
2010 to June 30, 2012. These
sequencing methods are highly
comprehensive and capable of finding
novel mutations. Sequencing results
are reported via a supplemental
report to hospitals and primary care
providers. If only 1 mutation is
identified, the newborn is considered
a screening test–negative carrier, and
parents and the primary care
provider are sent letters describing
the infant’s carrier status. Parents of
carriers are offered free telephone
genetic counseling in Spanish or
English. If $2 mutations (as defined
in Fig 310–12) are identified after
sequencing, primary care providers
are contacted by telephone to arrange
referral to a CFC for genetic counseling
of parents, and sweat chloride tests
(SCTs) and other diagnostic tests of
the child. Parents are sent a letter and
pamphlet with information about the
positive screening results and the
need for confirmatory SCTs.
Pediatric CFCs in California routinely
report all subjects diagnosed with
CF with negative CF NBS test results
to GDSP as part of their quality
assurance procedures. The reasons
why CF was missed are thoroughly
investigated, and they may include
1063
FIGURE 2
The California CF NBS program flowchart: July 16, 2007, to June 30, 2012. aMissed CF cases. bAs determined by DNA sequencing laboratory. cBegan parent
testing as part of the screening program to determine phase in July 2010. dStopped referring 1 panel mutation in combination with only a (TG)11‐5T
variant starting June 2011.
performing multiplex ligationdependent probe amplification13
(MRC-Holland, Amsterdam, The
Netherlands) to determine gross
deletions or duplications when 1 or
no mutation was detected. These
aforementioned methods meet or
exceed implementation, design, and
reporting guidelines for CF NBS
programs.14
SCT results and diagnostic and
clinical follow-up data are collected
from CFCs via GDSP’s secure, online
screening information system. SCTs
are performed by CFF-accredited
laboratories according to current
standards15 and guidelines.16 Parents
are encouraged to provide salt
supplementation and hydration to the
infant before testing. Follow-up is
conducted with the use of guidelines
developed by CFCs and GDSP.17
Diagnostic services and medical care
1064
for uninsured families are covered by
California Children’s Services.
CFCs make a determination for a final
diagnosis of CF or CRMS by using
published guidelines.5,18 DNA testing
on biological parents of screening
test–positive infants with nonelevated
SCT values was recommended and
then offered by GDSP starting July 1,
2010, to determine the cis/trans
mutation phase (ie, on same/different
chromosomes, respectively). In 2014,
all CF screening test–positive and
false-negative CF cases were reviewed
for accuracy and consistency to
confirm the diagnoses of CF, CRMS,
and CF carrier. Newborns with
positive CF screening test results were
considered to have CRMS unless there
was evidence of $1 of the following
CF diagnostic criteria: 2 identified
CF-causing mutations (per the
Clinical and Functional Translation of
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CFTR Project [CFTR2]),19 a SCT
value $60 mmol/L, last fecal elastase
value #200 µg/g, neonatal meconium
ileus, a sibling with the same
genotype and positive SCT results
diagnosed with CF, or physician’s
discretion. A carrier diagnosis was
given when known mutations/
variants were documented to be in
the cis phase according to parent
studies or the literature.
The CF prevalence, detection rate,
and positive predictive value were
estimated overall and according to
5 race/ethnicity categories. Age at
blood collection, IRT result, panel
mutation result, sequencing result,
referral, first evaluation, first SCT,
diagnosis, and treatment initiation
were reported overall and according
to panel- and sequence-positive
groups by using the 25th, 50th, and
75th percentiles. The study protocol
KHARRAZI et al
TABLE 1 Chronology of the CFTR Mutation Panels Used by the California NBS Program: July 16,
2007, to June 30, 2012
Date Added
July 16, 2007
October 4, 2007
December 12, 2007
August 12, 2008
Mutations Added or Removed–cDNA
Name (Legacy Name)
No.
c.164+2T.A (296+2T.A)
c.254G.A (G85E)
c.274-1G.A (406-1G.A)
c.489+1G.T (621+1G.T)
c.579+1G.T (711+1G.T)
c.595C.T (H199Y)
c.933_935delCTT (F311del)
c.1000C.T (R334W)
c.1519_1521delATC (I507del)
c.1521_1523delCTT (F508del)
c.1585-1G.A (1717-1G.A)
c.1624G.T (G5423)
c.1646G.A (S549N)
c.1652G.A (G551D)
c.1657C.T (R5533)
c.1675G.A (A559T)
c.1680-1G.A (1812-1G.A)
c.1973-1985del13insAGAAA (2105-2117del13insAGAAA)
c.2175_2176insA (2307insA)
c.2988+1G.A (3120+1G.A)
c.3196C.T (R1066C)
c.3266G.A (W10893)
c.3485G.T (R11623)
c.3611G.A (W12043 [3743G.A])
c.3717+12191C.T (3849+10kbC.T)
c.3744delA (3876delA)
c.3846G.A (W12823)
c.3909C.G (N1303K)
c.1153_1154insAT (1288insTA)
c.54-5940_273+10250del21kb (CFTRdele2,3(21kb))
c.531delT (663delT)
c.613C.T (P205S)
c.803delA (935delA)
c.1475C.T (S492F)
c.1923_1931del9insA (2055del9.A)
c.223C.T (R753)
c.293A.G (Q98R)
c.3140-26A.G (3272-26A.G)
c.988G.T (G3303)
c.3612G.A (W12043 [3744G.A])
c.3659delC (3791delC)
c.164+2T.A (296+2T.A), removed
28
29
38
40
cDNA, complementary DNA.
was approved by the California
Health and Human Services Agency
Committee for the Protection of
Human Subjects (project no.
12-0600354).
RESULTS
Figure 2 presents the number of
infants in each step of the program.
During the first 5 years, 2 573 293
newborns had an IRT test completed,
representing 98.8% of births. Of
these, 40 646 (1.6%) had an IRT
PEDIATRICS Volume 136, number 6, December 2015
value $62 ng/mL and were tested for
28 to 40 CFTR mutations. The allelic
frequency of these mutations is
found in Supplemental Table 8. No
panel mutations were identified in
38 149 (93.9%) hypertrypsinogenemic
newborns. Two panel mutations were
identified in 194 (0.5%), and these
newborns were referred to a CFC for
SCT and follow-up. Of the 174 (89.7%)
infants with 2 panel mutations who
underwent SCT, 162 (93.1%) had
initial valid positive test results
($60 mmol/L).
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Of the hypertrypsinogenemic
newborns, 2303 (5.7%) had 1 panel
mutation, and their blood spots
subsequently underwent DNA
sequencing. After sequencing,
1485 (64.5%) newborns still had only
1 mutation identified, and telephone
genetic counseling was offered to
these parents. One or more parents of
180 (12.1%) infants received such
counseling.
Two or more mutations were
identified in 818 (35.5%) newborns
(64 had $3 mutations) after
sequencing and were referred to a
CFC for SCT and follow-up. Of these,
77 (9.4%) had an initial valid positive
SCT result, and 76 were diagnosed
with CF at ,6 months of age (median
age: 51 days; 25th–75th percentile:
42–64 days). Of the 818 newborns,
741 (90.6%) had a nonpositive initial
valid SCT result (,60 mmol/L) and
were followed up by a CFC. To date,
132 (17.8%) of these newborns
were determined to be CF carriers
(Fig 2). Of the 741 newborns,
74 (10.0%) have been diagnosed with
CF (median age: 129.5 days; 25th–75th
percentile: 61–272 days) with the
remaining noncarriers given an initial
CRMS diagnosis. Twenty initial CRMS
case subjects had their diagnosis
changed to CF at .6 months of age
(Table 2). CRMS remained the
diagnosis for 533 (71.9%) children;
47 (8.8%) of these children had a
maximum SCT value in the
intermediate range (40–59 mmol/L).
A typical child with CRMS had a
high IRT value, 1 panel mutation, and
$1 mutation/variant from DNA
sequencing in the trans phase and a
maximum SCT result ,60 mmol/L.
Table 3 displays the median age at
blood collection, IRT test results,
panel mutation test results, and
sequencing results for all CF NBS
screening test–positive children; the
data are stratified according to
screening step. Typically, newborns
had an IRT result by 5 days of age,
and if the IRT level was $62 ng/mL,
the mutation panel was completed by
1065
24 days, respectively. Seventy-five
percent of infants identified according
to sequencing results were evaluated
at a CFC by 60 days of age, with a
median age at diagnosis of 148 days.
FIGURE 3
Definition of a CFTR mutation from DNA sequence testing used by the California NBS
program: July 16, 2007, to June 30, 2012. NCBI,
National Center for Biotechnology Information.
16 days. For those with only 1 panel
mutation, sequencing results were
available at a median age of 36 days.
The ages at referral, first evaluation
at a CFC, first SCT result, diagnosis,
and treatment initiation data are also
given in Table 3. Newborns were
referred within 2 days of being
reported as screening test–positive.
Most (75%) panel-positive cases
were evaluated at a CFC when the
child was #30 days old, with a
median age at diagnosis and
treatment initiation of 25 and
Thirteen deaths occurred among
the 1012 children who were CF
screening test–positive. Five died (of
prematurity and/or malformations)
before follow-up could be completed,
and 8 died after referral. Four of
these deaths were likely CF related
(ages 1, 8, 12, and 36 months)
(Supplemental Table 9).
In 5 years, GDSP has thus far
identified 1617 CF carriers (1485
screening test–negative and 132
screening test–positive children); 533
CRMS cases; and 373 CF cases (194
[∼39 per year] with 2 mutations from
the panel in step 2, 151 [∼30 per
year] infants by sequencing in step
3 (allelic mutation frequency in
Supplemental Table 10), and 28
[∼6 per year] screening test–negative).
TABLE 2 Genotype of 20 Children According to Age Diagnosis Was Changed From CRMS to CF in
the California NBS Program: July 16, 2007, to June 30, 2012
Genotypea cDNA Name
(Legacy Name)
No. of
Patients
c.1521_1523delCTT (F508del) / c.[1210–12[5]];[1210-34TG[13]]
(IVS8 (TG)13-5T)c
5
c.1521_1523delCTT (F508del) / c.3454G.C (D1152H)c
2
Age in Years at
Diagnostic Changeb
c.1521_1523delCTT (F508del) / c.350G.A (R117H)
2
c.223C.T (R753) / c.[1210–12[5]];[1210-34TG[13]]
(IVS8 (TG)13-5T)c
c.2988+1G.A (3120+1G.A) / c.164+28A.G (296+28A.G)e
c.1521_1523delCTT (F508del) / c.226C.A (L32M)e
c.1521_1523delCTT (F508del) / c.3475T.C (S1159P)e
c.933_935delCTT (delF311)e / c.[1210–12[5]];[1210-34TG[11]]
(IVS8 (TG)11-5T)f
c.531delT (663delT) / c.314T.A (I105N)e
c.1521_1523delCTT (F508del) / c.1841A.G (D614G)e
c.1521_1523delCTT (F508del) / c.290T.C (V97A)e
c.1519_1521delATC (I507del) / c.[1210–12[5]];[1210-34TG[12]]
(IVS8 (TG)12-5T)c
c.1624G.T (G5423) / c.3454G.C (D1152H)c
c.2988+1G.A (3120+1G.A) / c.[1210–12[5]];[1210-34TG[12]]
(IVS 8 (TG)12-5T)c
1
(n
(n
(n
(n
(n
(n
(n
1
1
1
1
1
1d
2
2
2
1
1
1
1
3
3
3
4
1
1
5
5
c
1
3
4
0.5d
2
1
2d
=
=
=
=
=
=
=
2)
1)
2)
1)
1)
1)
1)
a
CF-causing mutation according to CFTR2,19 unless noted.
Diagnosis change from CRMS to CF due to positive SCT results ($60 mmol/L), unless noted.
c Mutation of varying clinical consequence according to CFTR2.
d Diagnosis change due to abnormal fecal elastase results (#200 µg/g).
e Mutation not evaluated by CFTR2.
f Mutation is non–CF-causing according to CFTR2.
b
1066
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Of these missed cases, 14 (50%) had
an IRT value below the cutoff,
9 (32.1%) had no panel mutations
identified, and 5 (17.9%) did not have
a second mutation detected after
sequencing (Table 4).
Table 5 illustrates the 373 CF cases
distributed according to the
6 diagnostic review criteria used. A
total of 70.8% of the CF cases met $2
criteria. Small percentages had at
least 1 SCT result $60 mmol/L
(11.5%) or 2 CF-causing mutations
(8.9%) as the sole criterion. The
remainder of the CF cases (8.8%)
were diagnosed based solely on other
clinical evidence or physician’s
discretion. Overall, 53 (14.2%) of CF
case subjects had meconium ileus (43
detected and 10 missed by the
screening program).
Table 6 provides selected population
and screening statistics. CF birth
prevalence was 1 in 6899 overall, 1 in
4162 in non-Hispanic white subjects,
1 in 9259 in Hispanic subjects, and
1 in 9071 in African-American
subjects. The overall case detection
rate and positive predictive value for
the program were 92% and 34%,
respectively. Detection rates were
91% to 100% for California’s 3 main
race/ethnicity groups.
Over the study period, 303 different
CFTR mutations were identified,
including 78 novel variants. Of 85
children carrying a novel variant,
21 (24.7%) have been diagnosed with
CF to date.
DISCUSSION
This 5-year analysis from the
California CF program has many
strengths. The findings were derived
from a diverse and large number of
screened newborns (.2.5 million),
and genotyping as part of screening
was comprehensive in terms of
mutations and Intron 8 Poly (T) Tract
(IVS 8) status before referral to CFCs.
This screening provided timely,
high-quality genotype information to
CFC staff so that important decisions
could be made regarding clinical
KHARRAZI et al
TABLE 3 Time From Birth to Critical Screening Steps and Critical Follow-up Steps According to CF Screening Test–Positive Step in the California NBS
Program: July 16, 2007, to June 30, 2012
Screening and Follow-up Step
Total (N = 1012)
Time from birth to critical screening steps
Age at blood spot collection, h
Age at IRT test result (step 1)
Age at panel result (step 2)
Age at sequencing result (step 3)
Time from birth to critical follow-up steps
Age at referral
Age at first evaluation
Age at first SCT
Age at diagnosis
Age at treatment initiation
Panel Positive (n = 194)
Sequencing Positive (n = 818)
Median
25th%–75th%
Median
25th%–75th%
Median
26
5
16
—
23–35
4–6
14–18
—
29
5
16
—
24–41
4–7
14–19
—
26
5
16
36
34
47
56
88
53
26–43
35–61
42–78
46–248
34–94
18
24
46.5
25
24
16–20
18–32
28–85
18–41
19–35
37
51
57
148
67
25th%–75th%
23–34
4–6
14–19
29–43
31–45
41–64
44–77
60–296
48–152.5
All values are in days unless otherwise noted. —, not applicable.
care, testing, and treatment,
especially now that mutation-specific
therapy technology is advancing.20
The clinical diagnosis of CF was
reviewed and verified by using a set
of standard criteria. The length of the
follow-up period for screening
test–positive individuals extended
into early childhood, with CF
diagnosed in children as old as
7 years. GDSP made repeated efforts
to ensure thorough reporting of all CF
case reports. Despite these efforts,
follow-up of CRMS cases was less
complete than for CF cases after 1 year
of age. Because children who become
symptomatic presumably return to a
CFC, thereby triggering reporting to
TABLE 4 Numbers and Selected Characteristics of 28 False-Negative CF Cases According to Screening Step in the California NBS Program: July 16, 2007,
to June 30, 2012
Screening Step
1. IRT below cutoff
N
IRT Level (ng/mL)a/Genotype, cDNA Name (Legacy Name)
Race/Ethnicity
Reason for CF Diagnosis
14
9 / (mutations not identified)
9 / c.1727G.C (G576A)/ c.2002C.T (R668C)
16 / c.1521_1523delCTT (F508del)/ c.1624G.T (G5423)
28 / c.1521_1523delCTT (F508del)/ c.1521_1523delCTT (F508del)
28 / c.14C.T (P5L)/ c.870-7_870-5delTTT (1002-7delTTT)
29 / (mutations not identified)
31 / c.1521_1523delCTT (F508del)/ c.2175_2176insA (2307insA)
31 / (mutation not identified)/ c.[1210–12[5]];[1210-34TG[13]]
(IVS 8 (TG)13-5T)
34 / c.1521_1523delCTT (F508del)/ c.933_935delCTT (F311del)
48 / c.1521_1523delCTT (F508del)/ c.1521_1523delCTT (F508del)
51 / c.1521_1523delCTT (F508del)/ c.1521_1523delCTT (F508del)
52 / (mutations not identified)
54 / c.1521_1523delCTT (F508del)/ c.1792_1798delAAAACTA
(1924del7)
58 / c.303_304insA (435insA)/ c.617T.G (L206W)
c.2822delT/ c.2822delT (n = 3)
c.1153_1154insAT (1288insTA)/ c.1153_1154insAT (1288insTA)b
c.165-3C.T (297-3C.T)/ c.4147_4148insA (4279insA)/
c.4201G.T (E14013)
c.220C.T (R74W)/ c.601G.A (V201M)/ c.2562T.G (T854T or
2694T/G)/ c.[1210–12[5]];[1210-34TG[13]] (IVS 8 (TG)13-5T)
c.579+5G.T (711+5G-.T)/ c.948delT (1078delT)
c.3368-2A.G (3500-2A-.G)/ c.1679+1643G.T (1811+1643G.T)
c.1792_1798delAAAACTA (1924del7)/ c.2668C.T (Q8903)
c.1521_1523delCTT (F508del)/ (Ex6b_10dup)
c.1652G.A (G551D)/ c.3964-78_4242+577del (CFTRdel22,23)
c.1519_1521delATC (I507del)/ c.1680-877G.Tc
c.1521_1523delCTT (F508del)/ c.328G.C (D110H)d
c.1521_1523delCTT (F508del)/ (mutation not identified)
White (n = 5)
Hispanic (n = 3)
Other/multiple (n = 6)
Meconium ileus (n = 2)
Family history (n = 2)
Symptoms (n = 12)
Hispanic (n = 7)
Other/multiple (n = 2)
Meconium ileus (n = 4)
Family history (n = 4)
Symptoms (n = 8)
White (n = 3)
Hispanic (n = 1)
Unknown (n = 1)
Meconium ileus (n = 4)
Family history (n = 2)
Symptoms (n = 3)
2. No mutations on panel
9
3. Second mutation not detected by
using DNA sequencing
5
cDNA, complementary DNA.
a IRT level listed only when below the cutoff value (62 ng/mL).
b Case missed before mutation was added to the California mutation panel.
c Case missed initially by the DNA sequencing because testing was incomplete for Intron 12 (legacy Intron 11) but subsequently found on retesting of these blood spots.
d Case missed by the DNA sequencing test for unknown reasons.
PEDIATRICS Volume 136, number 6, December 2015
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1067
7.5
2.4
0.5
0.8
33.8
14.2
3.2
8.9
1.3
1.3
0.3
5.4
11.5
1.9
0.5
6.4
100.0
—
N
28
9
2
3
126
53
12
33
5
5
1
20
43
7
2
24
373
—
Physician’s Discretion (Per Symptoms)
No
No
No
No
No
No
No
No
No
No
Yes
No
No
No
No
Yes
25
6.7%
Unlike traditional 2-step IRT-DNA
programs, which consider any
hypertrypsinogenemic newborn with
$1 CFTR mutation as screening
test–positive, the California program
required $2 mutations to be
considered positive. CFTR sequencing,
as a third step conducted in ,1 in
1000 infants screened, reduced
the number of CF carriers referred
for SCT by two-thirds (1485 fewer
newborns) compared with the 2-step
model.
1068
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
No
2
0.5%
Yes
No
Yes
No
Yes
No
Yes
No
Yes
No
No
Yes
No
Yes
No
No
200
53.6%
Using a broad definition for a
second CFTR mutation, 35% of
hypertrypsinogenemic infants with
1 mutation from the California panel
had a second mutation/variant (or
more) identified from sequencing.
The findings of 303 different CFTR
mutations, including 78 novel
variants, indicate great population
heterogeneity and novelty. Previously,
an in-depth analysis of a 3-year
subset of the current data showed
that a significant portion (10 of
55 [18%]) of the novel mutations
were likely CF-causing,21 a finding that
is consistent with this 5-year study.
CF-causing mutation according to CFTR2.19
a
Yes
Yes
Yes
Yes
No
No
No
No
Yes
Yes
Yes
No
No
No
No
No
53
14.2%
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
No
266
71.3%
Yes
Yes
No
No
Yes
Yes
No
No
Yes
Yes
No
Yes
Yes
No
No
No
289
77.5%
Sibling With the Same Mutations and
Positive SCT Result
Fecal Elastase Level ,200 µg/g
SCT Result $60 mmol/L
Meconium Ileus
$2 CF-Causing Mutationsa
TABLE 5 Frequency of CF (n = 373) According to 6 Nonexclusive Diagnostic Criteria (Includes 28 Missed Cases) in the California NBS Program: July 16, 2007, to June 30, 2012
%
GDSP, underreporting of CF was
probably small.
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The presence of $2 mutations in all
screening test–positive infants by
definition prompted CFCs to
implement a diagnostic follow-up
period of at least 1 year in
asymptomatic infants with initial SCT
values ,60 mmol/L. This method
resulted in detection of 74 (27.3%)
more CF cases, the diagnosis in 20
occurring after 6 months of age; it
also revealed that in a portion of
screening test–positive infants, SCT
and/or fecal elastase values changed
into the CF diagnostic range as the
child aged. Many of the mutations
associated with this change were
of varying clinical consequence
(Table 2).19 A recent study of newborns
with an initial CRMS diagnosis followed
up for 3 years by 8 CFCs outside
California found that 2 (3%) of 75
obtained a subsequent diagnosis of
CF due to elevated SCT values,22 a
KHARRAZI et al
TABLE 6 Selected CF Population and Screening Statistics According to Race/Ethnicity in the California NBS Program: July 16, 2007, to June 30, 2012
Race/Ethnicity
Live Births
Screened
CF Screening
Test–Positive Subjects
CF Cases Detected
From Screening
Test– Positive
Subjects
False-Negative
CF Cases
Prevalence at
Birth of CF
CF Case Detection
Rate, %
Positive Predictive
Value, %
Non-Hispanic white
Hispanic
African American
Other/multiple
Unknown
Total
657 597
1 092 619
136 058
434 174
25 629
2 573 293
413
333
70
174
4
1012
150
107
15
71
2
345
8
11
0
8
1
28
1/4162
1/9259
1/9071
1/5496
1/8543
1/6899
95
91
100
90
67
92
36
32
21
41
50
34
figure consistent with that reported
here in California. Longer term
follow-up studies (probably into
adulthood) are needed to better
understand the factors that
contribute to evolution of the CF
phenotype.
In an attempt to focus screening on
severe CF cases, we split mutation
testing into 2 steps (panel and
sequencing) and restricted panel
mutations to those that we found to
be clearly CF-causing in the California
population. Theoretically, this
approach has maximized severe CF
case identification in the panel step,
compared with most other programs.
According to CFTR2, 37 panel
mutations are CF-causing, and 3 have
not yet been evaluated; this outcome
highlights the importance at a
regional level of including mutations
found in confirmed clinical cases in
the screened population and not
solely basing the choice of mutations
on those evaluated by CFTR2. In the
sequencing step, a broad definition of
mutation was used (Fig 3); although
this definition enhanced sensitivity,
its use led to a diagnosis of CRMS 1.5
times more common than CF in our
screening test–positive population
(533 vs 345, respectively). With
traditional IRT-DNA algorithms, these
same CRMS cases and others are
considered screening test–positive
and are referred for SCT; however,
after receiving SCT results
,30 mmol/L, most are misdiagnosed
as carriers because of a lack of
comprehensive genotyping. It is
potentially very stressful for parents
to learn that their child is screening
test–positive and then be told by the
CFC that their child does not
currently exhibit signs and symptoms
of CF but may do so in the future.23
California uses follow-up guidelines
that encourage CFC visits quarterly
for at least 1 year for children with
CRMS; thus, SCTs can be repeated,
symptoms evaluated, and other
testing and monitoring performed.
The short- and long-term
psychosocial effects on parents and
costs to families of caring for a child
with CRMS must be evaluated, along
with efforts to reduce psychosocial
distress. By continuing to limit the
definition of screening test–positive
results to only those genotypes that
cause CF using knowledge gained
over time from the screening
program, CFTR2, and elsewhere, the
California algorithm will be able to
clarify the value of identifying infants
with CRMS as well as continue to
adjust the referral algorithm by
removing benign variants.24
No CF NBS algorithm will detect all
cases of CF. The detection rate of CF
in California (total 345 [69 per year])
was 92%, exceeding program
expectations of 90%. This rate
includes infants with meconium ileus.
Because cases of meconium ileus
are identified in the absence of
screening, removing these infants
from the calculation produces a
detection rate of 95%. Reports from
other programs typically range from
92% to 98% (Table 7)25–29; however,
these rates are likely overestimated
due to shorter follow-up periods
and/or less rigorous identification of
missed cases than the present study.
One-half of the missed cases (14 of
28) had an IRT value below the cutoff
of 62 ng/mL, corresponding to the top
1.6th percentile. Lowering the cutoff
to 49.4 ng/mL, which corresponds
to the top fourth percentile used by
many states,4 would have resulted
in 4 fewer cases being missed by the
IRT step (or ,1 per year). The costs
TABLE 7 CF Case Detection Rate and Positive Predictive Value for Other Selected NBS Programs
Location
Algorithm
CF Case Detection Rate, %
Positive Predictive Value, %
Reference
New South Wales, Australia
New South Wales, Australia
IRT-IRT
IRT-DNAa
92
94
5
28
Massachusetts
Wisconsin
Coloradob
New York
IRT-DNA
IRT-DNA
IRT-IRT
IRT-DNA
98
95
93
98
9
9
5
3
25
V. Wiley, PhD, personal communication, 2015;
B. Wilcken, MD, personal communication, 2015
26
27
28
29
a
b
Based on a c.1521_1523delCTT (F508del) only mutation panel.
Figures exclude meconium ileus cases.
PEDIATRICS Volume 136, number 6, December 2015
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1069
and inefficiencies to the program that
would come with lowering the IRT
cutoff value to the top fourth
percentile (estimated by GDSP to be
approximately twice the costs for
mutation testing and genetic
counseling for carriers and likely
higher costs for additional referrals)
are considered excessive compared
with the small gain in sensitivity
(1%–2%); they would also conflict
with the program’s goal of equally
maximizing both sensitivity and
specificity. In the first 5 years, there
was 1 mutation missed by the panel
that appeared in .1 unrelated
subjects (c.2822delT/c.2822delT
found in 3 Hispanic subjects from
2 unrelated families) (Table 4),
suggesting that the program could
improve sensitivity ∼1% by adding
this mutation to California’s
40-mutation panel. The DNA sequencing
step missed only a small number of
subjects with unique gross insertions
or deletions as the second mutation.
The positive predictive value of
California’s 3-step program is 34%
(31% excluding infants with meconium
ileus). Reports from other programs
typically range from 5% to 9%
(Table 7). Reducing false-positive
findings produces large savings in
program, medical, family, and societal
costs, despite costs of US $500 to
$1000 incurred by the program per
DNA sequencing test. The California
findings are consistent with those
modeled in a cost-effectiveness study
of 4 different CF NBS algorithms.30
However, 2 recent studies31,32 suggest
that IRT/pancreatitis–associated
protein algorithms may be even more
cost-effective than California’s 3-step
algorithm.
Age at reporting CF NBS results and
at making a CF diagnosis are
2 challenging areas for the California
program. CFF guidelines instruct that
SCT should be performed by 2 to
4 weeks of age and diagnosis should
occur by 1 to 2 months of age.18 The
literature suggests that subjects with
CF diagnosed within 2 months of life
1070
are most likely to benefit from early
interventions.33 In California, 74.5%
of CF NBS-positive newborns were
seen by CFCs before age 2 months;
this time frame was largely influenced
by the 2 to 3 weeks needed to complete
DNA sequencing. Improvements have
been made to reduce this time by
conducting both mutation panel and
DNA sequence testing in the same
physical location and in reducing assay
testing time. New technologies, such as
next-generation sequencing, may be
valuable in further shortening this time.
population is meeting its goals of high
detection and low false-positive
results. The follow-up of newborns
with $2 mutations showed that CF
cases are not always apparent in the
first few months of life. Reliance on
an initial SCT result $60 mmol/L (or
even $30 mmol/L) to distinguish true
CF cases from carriers in the absence
of comprehensive genotyping is likely
to miss a small portion of CF cases.
The uptake of genetic counseling by
parents of nearly 1500 nonreferred
CF carriers identified by the program
was 12.1%. It is unknown why so
many parents are not using the
telephone genetic counseling service,
designed according to California’s
NBS follow-up of hemoglobinopathy
traits.34 Given the large scale of
prenatal CF carrier testing being
conducted,35 many parents may have
already received CF genetic counseling.
The program has not evaluated the
effectiveness of the telephone genetic
counseling program, although such a
review is being considered.
Dr Lisa Prach (GDSP) assisted with
analyses and an early version of the
article. Ruth Koepke (GDSP) helped
collect data from CFCs in the first few
years of the California CF NBS
program. Dr Iris Schrijver (Stanford
Molecular Pathology Laboratory) and
Steven Keiles (Ambry Genetics)
oversaw CFTR mutation testing and
results reporting, and they consulted
on mutation panel derivation.
Drs George Helmer and John Eastman
(GDSP Genetic Disease Laboratory)
helped in the development, validation,
and implementation of laboratory
testing methods. Dr Richard Parad
(Harvard Medical School) provided
useful information on implementation
of the California CF NBS Program.
Given that an additional 6.2% of CF
cases identified to date were
diagnosed after 6 months of age, CF
NBS programs that do not conduct
comprehensive genotyping (and
which rely mainly on elevated SCT
values and symptoms at initial followup to make a diagnosis of CF) may be
mislabeling some infants who actually
have CF as CF carriers. It is important
that the genetic counseling that follows
diagnostic testing emphasize that CF
is still possible in these infants and
that the appearance of any suggestive
CF signs and symptoms as the child
ages should result in prompt referral
to a CFC for evaluation and
comprehensive genotyping.
CONCLUSIONS
After 5 years, the 3-step (IRT–40mutation panel–DNA sequencing)
CF NBS model used in a racially
and ethnically diverse California
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ACKNOWLEDGMENTS
The following CFCs, center directors,
and staff clinically followed-up CF
NBS-positive newborns; provided the
clinical data presented in the article;
commented and provided input on
multiple versions of the manuscript;
and, together with the staff of the
GDSP, comprise the California Cystic
Fibrosis Newborn Screening
Consortium. Children’s Hospital Los
Angeles, Los Angeles, California:
Dr Thomas Keens, Dr Danieli B. Salinas,
Maria Carmen Reyes, and Cynthia
Leyva; Rady Children’s Hospital,
San Diego, California: Dr Mark Pian,
Kimberly Mollin, and Yolanda Perez;
Department of Pediatrics, Loma Linda
University School of Medicine, Loma
Linda, California: Dr Yvonne Fanous,
Dr Harry Opsimos, Dr Kimberly N.
Otsuka, and Nancy Wheeler-Dobrota;
Children’s Hospital Oakland, Oakland,
KHARRAZI et al
California: Dr Karen Ann Hardy and
Deborah Kaley; Center for Excellence
in Pulmonary Biology, Stanford
University, Palo Alto, California:
Dr Carlos E. Milla, Dr Richard Moss, and
Dr Jacquelyn M. Zirbes; Sutter Cystic
Fibrosis Center, Sutter Memorial
Hospital, Sacramento, California:
Dr Bradley Chipps, Dr Myrza Perez,
Susan O’Bra, and Kasey Pearson;
Kaiser Permanente Los Angeles
Medical Center, Los Angeles,
California: Dr Muhammad M. Saeed;
Children’s Hospital Central California,
Madera, California: Dr Reddivalam
Sudhakar and Susan Lehto; University
of California, San Francisco Medical
Center, San Francisco, California:
Dr Dennis Nielson, Diana Dawson, and
Martha Richards; Kaiser Permanente
Northern California, Oakland,
California: Dr Gregory F. Shay and
Mary Seastrand; University of
California Davis Medical Center,
Sacramento, California: Dr Ruth
McDonald, Dr Sanjay Jhawar, and Kim
Franz; Division of Pediatric
Pulmonology, Children’s Hospital of
Orange County, Orange, California:
Dr Bruce Nickerson and Dawn
McRitchie; Ventura County Medical
Center, Ventura, California:
Dr Christopher Landon and Ann
Thompson; Pediatric Pulmonary
Division, Miller Children’s Hospital,
Long Beach, California: Dr Eliezer
Nussbaum, Dr Terry Chin, and Jill M.
Edwards; Naval Medical Center, San
Diego, California: Dr Henry Wojtczak;
Department of Pediatrics, Division of
Pediatric Pulmonology, Mattel
Children’s Hospital, University of
California, Los Angeles, California:
Dr Marlyn S. Woo and Elaine
Harrington; and Kaiser Permanente,
San Diego, California: Susan D. Noetzel.
ABBREVIATIONS
CF: cystic fibrosis
CFC: cystic fibrosis specialty care
center
CFF: Cystic Fibrosis Foundation
CFTR: cystic fibrosis
transmembrane
conductance regulator
CFTR2: The Clinical and Functional
Translation of CFTR
Project
CRMS: cystic fibrosis
transmembrane
conductance
regulator–related
metabolic syndrome
GDSP: California Department of
Public Health Genetic
Disease Screening Program
IRT: immunoreactive trypsinogen
NBS: newborn screening
SCT: sweat chloride test
Address correspondence to Martin Kharrazi, PhD, MPH, Environmental Health Investigations Branch, California Department of Public Health, 850 Marina Bay Pkwy,
Building P, Floor 3, Richmond, CA 94804. E-mail: marty.kharrazi@cdph.ca.gov
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2015 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found on page 1181, and online at www.pediatrics.org/cgi/doi/10.1542/peds.2015-3490.
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KHARRAZI et al
Newborn Screening for Cystic Fibrosis in California
Martin Kharrazi, Juan Yang, Tracey Bishop, Shellye Lessing, Suzanne Young, Steven
Graham, Michelle Pearl, Helen Chow, Thomson Ho, Robert Currier, Leslie Gaffney,
Lisa Feuchtbaum and on behalf of the California Cystic Fibrosis Newborn Screening
Consortium
Pediatrics 2015;136;1062; originally published online November 16, 2015;
DOI: 10.1542/peds.2015-0811
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2015 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Newborn Screening for Cystic Fibrosis in California
Martin Kharrazi, Juan Yang, Tracey Bishop, Shellye Lessing, Suzanne Young, Steven
Graham, Michelle Pearl, Helen Chow, Thomson Ho, Robert Currier, Leslie Gaffney,
Lisa Feuchtbaum and on behalf of the California Cystic Fibrosis Newborn Screening
Consortium
Pediatrics 2015;136;1062; originally published online November 16, 2015;
DOI: 10.1542/peds.2015-0811
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/136/6/1062.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2015 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on October 1, 2016