1

Supplemental Text 1. Observations of unexpected majority-genetic ancestry.

The test requisition form for our ECS lists three Asian ethnicity options (East, Southeast, and South Asian) and lists example countries of origin accompanying each option. We observed that those self-reporting as Southeast Asian typically had their majority genetic ancestry coming from the East Asian (EA) rather than South Asian (SA) component (Figure 1a, "E Asian", "SE Asian" and "S Asian" rows). There were both East Asians with majority South Asian genetic ancestry (4.7% of self-reporting East Asians) as well as South Asians with majority East Asian genetic ancestry (2.8% of South Asians). The largest proportion of individuals with majority-European ancestry (EUR) among the three Asian SREs was among the Southeast Asian group (3.9% of self-reporting Southeast Asians, compared to 2.0% of East Asians and 0.6% of South Asians). The majority genetic ancestry and self-reported ethnicity matched better for South Asians (96.3% of South Asians had majority genetic ancestry component of South Asian ancestry) compared to East Asians (93.0%).

Those self-reporting as Middle Eastern had majority genetic ancestry split mostly between Middle Eastern (59.2%, ME), South Asian (28.4%), European (10.2%) and Ashkenazi Jewish (1.7%, AJ) with the remaining ancestries each <1% (Figure 1a, "Mid. East" row). The large proportion of individuals with majority-South Asian genetic ancestry may arise from a technical limitation to strongly distinguish between Middle Eastern and South Asian ancestry when admixed with European ancestry.

Patients self-reporting as Ashkenazi Jewish had majority genetic ancestry coming from the Ashkenazi Jewish ancestry component for 80.2% of patients, from the European component for 16.8%, and from the Middle Eastern component for 2.7% of patients, with <1% with other majority-GAs (Figure 1a, "AJ" row). Since the AJ genetic ancestry distribution among the AJ is wide-ranging with a mode near 3/4 AJ genetic ancestry, those with majority-European genetic ancestry may still have substantial levels of AJ ancestry (SI Figure 1).

Self-reporting Northern Europeans had largely expected genetic ancestry, with 96.9% of Northern Europeans having majority genetic ancestry coming from the European component and 2.2% having majority-AJ genetic ancestry with the other majority-GAs at <1% of Northern Europeans (Figure 1a, "N. Eur." row).

Self-reporting Southern Europeans also had less expected genetic ancestry compared to Northern Europeans, with 84.0% of Southern Europeans having majority genetic ancestry coming from the European component, 13.5% from the Middle Eastern component, and 1.5% from the AJ component with the other majority-GAs at <1% of Southern Europeans (Figure 1a, "S. Eur." row).

For patients self-reporting as African or African-American, 90.7% had majority genetic ancestry from the African ancestry component (AF) and 6.3% had majority genetic ancestry from the European component (Figure 1a, "Afr. Am." row). As the African ancestry distribution among this self-reported ethnicity has a mode at around 80% with a secondary mode at 40%, the subpopulation with majority-European ancestry is still expected to have substantial African genetic ancestry (SI Figure 1). A subpopulation with admixture between Middle Eastern and African ancestry was also observed; 2.2% of patients self-reporting as African or African-American had majority genetic ancestry from the Middle Eastern genetic ancestry component.

Three subpopulations were observed among those self-reporting as Hispanic: 1) those with European-Native American admixture, 2) those with European-African American admixture, and 3) those with admixture from European, Native American (NA), and African sources. In this analysis, only two-way admixture was considered and those with strong evidence for more admixture sources were excluded (described in Methods). The levels of European and Native American ancestry in group (1) were wide

2

ranging, reflected in the observations that 72.1% of self-reported Hispanics had majority-European genetic ancestry and 24.4% had majority-Native American genetic ancestry (Figure 1a, "Hispanic" row). The African ancestry in group (2) was also wide ranging with a mode closer to 1/4th; 1.8% of Hispanics had majority-ancestry from the African ancestry component, yet many more had substantial African ancestry (SI Figure 1).

3

Supplemental Figure 1. Distribution of genetic ancestry in all self-reported ethnicity groups. Highlighted violin plots indicate the "expected" genetic ancestry for the given self-reported ethnicity. Each violin plot includes only those with ≥1/32 of the given genetic ancestry, with the numbers indicating the proportion of the self-reported ethnicity plotted as well as the absolute number. Subpopulations with fewer than 100 individuals were not shown. Vertical lines within the violin plot indicate the 25th, 50th, and 75th percentiles of genetic ancestry. The "any" self-reported ethnicity includes the whole study cohort.

Supplemental Figure 2. Same as Figure 2 but excluding “Mixed or Other Caucasian” patients. Supplemental Figure 3. (a and c) Distribution of self-reported ethnicities among those with medium genetic ancestry (a) and high genetic ancestry (c). Hatching indicates secondary self-reported ethnicities. Colors are indicated in panel (c), where the text overlay specifies the ethnicity indicated by the leftmost bar. (b and d) Comparison of ancestry-specific carrier rates among those with medium genetic ancestry (b) and high genetic ancestry (d) based on whether they self-reported the associated ethnicity (x-axis) or not (y-axis). Each dot represents a combination of a disease and an ancestry (e.g., cystic fibrosis in Europeans). Disease-ancestry-self-reported ethnicity combinations with no observed carriers in this dataset are shown on the axes.

Supplemental Figure 4. Variant frequency distribution in those with low vs medium or high guideline-related genetic ancestry. For the 16 conditions with ethnicity-specific guidelines (separate panels), patients with low genetic ancestry (left of panel) and medium or high genetic ancestry (right of panel) carry pathogenic variants at different frequencies (y-axis). The genetic ancestry was chosen to correspond to the ethnicity with a guideline (e.g., Ashkenzi Jewish for Gaucher disease). Each horizontal line represents a variant, with a blue line indicating a variant observed in only one of the two subpopulations (e.g., in the low genetic ancestry subpopulation but not in the medium or high genetic ancestry subpopulation) and a black trace spanning the subpopulations indicating a single variant present in both subpopulations often at different frequencies (hence the upward or downward slope of middle segment). For most conditions, the medium-or-high-genetic ancestry subpopulation exhibited smaller variant diversity (i.e., fewer horizontal lines on right side of each panel) compared to the low-genetic ancestry subpopulation, as expected if founder variants are present.

Supplemental Table 1. Diseases included in the analysis.

Supplemental Table 2. Variants excluded in carrier rate analysis.

Supplemental Table 3. Self-reported ethnicities, genetic ancestries, and guideline recommendations as analyzed in this study.

Supplemental Table 4. Carriers missed by ethnicity-specific carrier screening compared to pan-ethnic expanded carrier screening. Individuals carriers for multiple diseases were counted for each disease.

Supplemental Table 5. Distributions of frequencies for variants observed in the low vs. medium/high

genetic ancestry groups.

Supplemental Figure 1

Supplemental Figure 2

Supplemental Figure 3

Supplemental Figure 4

Kaseniit et al. Supplemental Tables Table S1

Table S1: Diseases included in the analysisDisease Gene21-hydroxylase-deficient congenital adrenal hyperplasia CYP21A2ABCC8-related hyperinsulinism ABCC8alpha thalassemia HBA1alpha-mannosidosis MAN2B1alpha-sarcoglycanopathy SGCAAndermann syndrome SLC12A6ARSACS SACSaspartylglycosaminuria AGAataxia with vitamin E deficiency TTPAataxia-telangiectasia ATMBardet-Biedl syndrome, BBS1-related BBS1Bardet-Biedl syndrome, BBS10-related BBS10beta-sarcoglycanopathy SGCBbiotinidase deficiency BTDBloom syndrome BLMCanavan disease ASPAcarnitine palmitoyltransferase IA deficiency CPT1Acarnitine palmitoyltransferase II deficiency CPT2cartilage-hair hypoplasia RMRPcitrullinemia type 1 ASS1CLN3-related neuronal ceroid lipofuscinosis CLN3CLN5-related neuronal ceroid lipofuscinosis CLN5Cohen syndrome VPS13Bcongenital disorder of glycosylation type Ia PMM2congenital disorder of glycosylation type Ib MPIcongenital Finnish nephrosis NPHS1Costeff optic atrophy syndrome OPA3cystic fibrosis CFTRcystinosis CTNSD-bifunctional protein deficiency HSD17B4familial dysautonomia IKBKAPfamilial Mediterranean fever MEFVFanconi anemia type C FANCCFKTN-related disorders FKTNfragile X syndrome FMR1galactosemia GALTGaucher disease GBAGJB2-related DFNB1 nonsyndromic hearing loss and deafnessGJB2glutaric acidemia type 1 GCDHglycogen storage disease type Ia G6PCglycogen storage disease type Ib SLC37A4glycogen storage disease type III AGLGRACILE syndrome BCS1LHADHA-related Disorders HADHAHb beta chain-related hemoglobinopathy HBBhereditary fructose intolerance ALDOBHerlitz junctional epidermolysis bullosa, LAMA3-related LAMA3Herlitz junctional epidermolysis bullosa, LAMB3-related LAMB3Herlitz junctional epidermolysis bullosa, LAMC2-related LAMC2hexosaminidase A deficiency HEXA

Kaseniit et al. Supplemental Tables Table S1

Table S1: Diseases included in the analysisDisease Genehomocystinuria caused by cystathionine beta-synthase deficiencyCBShypophosphatasia, autosomal recessive ALPLinclusion body myopathy 2 GNEisovaleric acidemia IVDJoubert syndrome 2 TMEM216Krabbe disease GALClipoamide dehydrogenase deficiency DLDmaple syrup urine disease type 1B BCKDHBmedium chain acyl-CoA dehydrogenase deficiency ACADMmegalencephalic leukoencephalopathy with subcortical cystsMLC1metachromatic leukodystrophy ARSAmucolipidosis IV MCOLN1mucopolysaccharidosis type I IDUAmuscle-eye-brain disease POMGNT1NEB-related nemaline myopathy NEBNiemann-Pick disease type C NPC1Niemann-Pick disease, SMPD1-associated SMPD1Nijmegen breakage syndrome NBNNorthern epilepsy CLN8PCDH15-related disorders PCDH15Pendred syndrome SLC26A4PEX1-related Zellweger syndrome spectrum PEX1phenylalanine hydroxylase deficiency PAHPKHD1-related autosomal recessive polycystic kidney diseasePKHD1polyglandular autoimmune syndrome type 1 AIREPompe disease GAAPPT1-related neuronal ceroid lipofuscinosis PPT1primary carnitine deficiency SLC22A5primary hyperoxaluria type 1 AGXTprimary hyperoxaluria type 2 GRHPRPROP1-related combined pituitary hormone deficiency PROP1pycnodysostosis CTSKrhizomelic chondrodysplasia punctata type 1 PEX7Salla disease SLC17A5Segawa syndrome THSjogren-Larsson syndrome ALDH3A2Smith-Lemli-Opitz syndrome DHCR7spinal muscular atrophy SMN1steroid-resistant nephrotic syndrome NPHS2sulfate transporter-related osteochondrodysplasia SLC26A2TPP1-related neuronal ceroid lipofuscinosis TPP1tyrosinemia type I FAHUsher syndrome type 3 CLRN1very long chain acyl-CoA dehydrogenase deficiency ACADVLWilson disease ATP7BX-linked juvenile retinoschisis RS1

Kaseniit et al. Supplemental Tables Table S2

Table S2: Variants excluded in carrier rate analysisNM_000500.7(CYP21A2):c.955C>T(Q319*) with duplicationNM_000060.2(BTD):c.1330G>C(D444H)NM_000277.1(PAH):c.688G>A(V230I)NM_014625.2(NPHS2):c.686G>A(R229Q)NM_004004.5(GJB2):c.101T>C(M34T)NM_002225.3(IVD):c.941C>T(A314V, aka A311V)NM_000492.3(CFTR):c.1210-7_1210-6delTT(aka IVS8-5T)

Kas

eniit

et a

l. S

uppl

emen

tal T

able

sTa

ble

S3

Tabl

e S3

: Sel

f-rep

orte

d et

hnic

ities

, gen

etic

anc

estr

ies,

and

gui

delin

e re

com

men

datio

ns a

s an

alyz

ed in

this

stu

dy.

Self-

repo

rted

eth

nici

ty o

n re

quis

ition

form

Self-

repo

rted

eth

nici

ty

used

in s

tudy

Rel

ated

/exp

ecte

d ge

netic

an

cest

ryA

CM

G te

rm (b

ased

on

Edw

ards

et a

l. O

bste

tric

s &

Gyn

ecol

ogy

2015

)A

CO

G te

rm (b

ased

on

com

mitt

e op

inio

n 69

1)

Gui

delin

e re

com

men

datio

ns a

s an

alyz

ed in

man

uscr

ipt (

in a

dditi

on to

pa

n-et

hnic

cys

tic fi

bros

is a

nd s

pina

l m

uscu

lar a

trop

hy s

cree

ning

)

Anc

estr

y-ba

sed

guid

elin

es a

s an

alyz

ed

in m

anus

crip

t (in

add

ition

to c

ystic

fib

rosi

s an

d sp

inal

mus

cula

r atr

ophy

sc

reen

ing)

Afri

can

or A

frica

n-A

mer

ican

Afri

can

or A

frica

n-A

mer

ican

Afri

can

Afri

can

Am

eric

ans

(rec

omm

enda

tion

for

hem

oglo

bino

path

ies

scre

enin

g)A

frica

n de

scen

t (re

com

men

datio

n fo

r he

mog

lobi

nopa

thie

s sc

reen

ing)

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

self-

repo

rting

as

Afri

can

or A

frica

n-A

mer

ican

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

with

med

ium

or h

ighe

r lev

els

of

Afri

can

GA

Ash

kena

zi J

ewis

hA

shke

nazi

Jew

ish

Ash

kena

zi J

ewis

hA

shke

nazi

Jew

ish

(rec

omm

enda

tion

for

vario

us d

isea

ses)

Ash

kena

zi J

ewis

h de

scen

t (r

ecom

men

datio

n fo

r var

ious

dis

ease

s)

For t

hose

sel

f-rep

ortin

g as

Ash

kena

zi

Jew

ish,

scr

eeni

ng fo

r: - h

exos

amin

idas

e A

de

ficie

ncy

- Can

avan

dis

ease

- fa

mili

al

dysa

uton

omia

- B

loom

syn

drom

e -

Gau

cher

dis

ease

- Fa

ncon

i ane

mia

type

C

- muc

olip

idos

is IV

- N

iem

ann-

Pic

k di

seas

e, S

MP

D1-

asso

ciat

ed -

AB

CC

8-re

late

d hy

perin

sulin

ism

- gl

ycog

en s

tora

ge

dise

ase

type

Ia -

Joub

ert s

yndr

ome

2 -

map

le s

yrup

urin

e di

seas

e ty

pe 1

B -

Ush

er s

yndr

ome

type

3 -

PC

DH

15-r

elat

ed

diso

rder

s

For t

hose

with

med

ium

or h

ighe

r lev

els

of

Ash

kena

zi J

ewis

h, s

cree

ning

for:

- he

xosa

min

idas

e A

def

icie

ncy

- Can

avan

di

seas

e - f

amili

al d

ysau

tono

mia

- B

loom

sy

ndro

me

- Gau

cher

dis

ease

- Fa

ncon

i an

emia

type

C -

muc

olip

idos

is IV

- N

iem

ann-

Pic

k di

seas

e, S

MP

D1-

asso

ciat

ed -

AB

CC

8-re

late

d hy

perin

sulin

ism

- gl

ycog

en s

tora

ge

dise

ase

type

Ia -

Joub

ert s

yndr

ome

2 -

map

le s

yrup

urin

e di

seas

e ty

pe 1

B -

Ush

er s

yndr

ome

type

3 -

PC

DH

15-r

elat

ed

diso

rder

s

His

pani

cH

ispa

nic

Nat

ive

Am

eric

an, E

urop

ean

N/A

His

pani

c de

scen

t (no

eth

nici

ty-s

peci

fic

reco

mm

enda

tion;

men

tions

that

po

pula

tion

has

incr

ease

d be

ta-

thal

asse

mia

car

rier r

ate)

Non

eN

one

Mid

dle

Eas

tern

Mid

dle

Eas

tern

Mid

dle

Eas

tern

N/A

Mid

dle

Eas

tern

des

cent

(rec

omm

enda

tion

for h

emog

lobi

nopa

thie

s sc

reen

ing)

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

self-

repo

rting

as

Mid

dle

Eas

tern

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

with

med

ium

or h

ighe

r lev

els

of

Mid

dle

Eas

tern

GA

Nor

ther

n E

urop

ean

Nor

ther

n E

urop

ean

Eur

opea

nN

/AN

/AN

one

Non

e

Sou

ther

n E

urop

ean

Sou

ther

n E

urop

ean

Eur

opea

nM

edite

rran

ean

(rec

omm

enda

tion

for

hem

oglo

bino

path

ies

scre

enin

g)M

edite

rran

ean

desc

ent (

reco

mm

enda

tion

for h

emog

lobi

nopa

thie

s sc

reen

ing)

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

self-

repo

rting

as

Sou

ther

n E

urop

ean

Non

e

Sou

th A

sian

Sou

th A

sian

Sou

th A

sian

N/A

N/A

Non

e

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

with

med

ium

or h

ighe

r lev

els

of

Sou

th A

sian

GA

Sou

thea

st A

sian

Sou

thea

st A

sian

Sou

th A

sian

, Eas

t Asi

anS

outh

east

Asi

an (r

ecom

men

datio

n fo

r he

mog

lobi

nopa

thie

s sc

reen

ing)

Sou

thea

st A

sian

des

cent

(r

ecom

men

datio

n fo

r hem

oglo

bino

path

ies

scre

enin

g)

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

self-

repo

rting

as

Sou

thea

st A

sian

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

with

med

ium

or h

ighe

r lev

els

of

Sou

th A

sian

GA

or E

ast A

sian

GA

Eas

t Asi

anE

ast A

sian

Eas

t Asi

anN

/AN

/AN

one

alph

a th

alas

sem

ia a

nd H

b be

ta c

hain

-re

late

d he

mog

lobi

nopa

thy

scre

enin

g fo

r th

ose

with

med

ium

or h

ighe

r lev

els

of E

ast

Asi

an G

A

N/A

Not

incl

uded

in s

tudy

N/A

N/A

Wes

t Ind

ian

desc

ent (

reco

mm

enda

tion

for

hem

oglo

bino

path

ies

scre

enin

g)N

/AN

/AM

ixed

or O

ther

Cau

casi

anM

ixed

or O

ther

Cau

casi

anN

/AN

/AN

/AN

/AN

/A

Fren

ch C

anad

ian

or C

ajun

Not

incl

uded

in s

tudy

N/A

Fren

ch-C

anad

ian

or C

ajun

des

cent

(r

ecom

men

datio

n fo

r Tay

-Sac

hs

scre

enin

g)

Fren

ch-C

anad

ian

or C

ajun

des

cent

(r

ecom

men

datio

n fo

r Tay

-Sac

hs

scre

enin

g)N

/AN

/AFi

nnis

hN

ot in

clud

ed in

stu

dyN

/AN

/AN

/AN

/AN

/AN

ativ

e A

mer

ican

Not

incl

uded

in s

tudy

N/A

N/A

N/A

N/A

N/A

Pac

ific

Isla

nder

Not

incl

uded

in s

tudy

N/A

N/A

N/A

N/A

N/A

Unk

now

nN

ot in

clud

ed in

stu

dyN

/AN

/AN

/AN

/AN

/A

Kas

eniit

et a

l. S

uppl

emen

tal T

able

sTa

ble

S4

Tabl

e S4

: Car

riers

mis

sed

by e

thni

city

-spe

cific

car

rier s

cree

ning

com

pare

d to

pan

-eth

nic

expa

nded

car

rier s

cree

ning

. Ind

ivid

uals

who

wer

e ca

rrie

rs fo

r m

ultip

le d

isea

ses

wer

e co

unte

d fo

r eac

h di

seas

e.

ethn

icity

carr

iers

id

entif

ied

carr

iers

m

isse

dpa

tient

s te

sted

carr

ier s

ensi

tivity

re

lativ

e to

pan

-et

hnic

EC

Sm

isse

d ca

rrie

rs re

lativ

e to

pan

-eth

nic

ECS

dise

ases

with

m

isse

d ca

rrie

rsto

p di

seas

es w

ith p

ropo

rtio

n of

all

mis

sed

carr

iers

Afri

can

or A

frica

n-A

mer

ican

2080

985

6996

67.9

0%32

.10%

87

21-h

ydro

xyla

se-d

efic

ient

con

geni

tal a

dren

al h

yper

plas

ia (8

.9%

) fr

agile

X s

yndr

ome

(8.5

%)

GJB

2-re

late

d D

FNB

1 no

nsyn

drom

ic h

earin

g lo

ss a

nd d

eafn

ess

(5.5

%)

Pom

pe d

isea

se (3

.6%

) g

alac

tose

mia

(3.1

%)

phe

nyla

lani

ne h

ydro

xyla

se d

efic

ienc

y (2

.6%

) c

onge

nita

l dis

orde

r of g

lyco

syla

tion

type

Ia (2

.5%

) g

luta

ric a

cide

mia

type

1 (2

.4%

) fa

mili

al M

edite

rran

ean

feve

r (2.

2%)

med

ium

cha

in a

cyl-C

oA d

ehyd

roge

nase

def

icie

ncy

(2.2

%)

Ash

kena

zi J

ewis

h28

2451

5296

8735

.40%

64.6

0%74

fam

ilial

Med

iterr

anea

n fe

ver (

19.2

%)

21-

hydr

oxyl

ase-

defic

ient

con

geni

tal a

dren

al h

yper

plas

ia (1

6.9%

) G

JB2-

rela

ted

DFN

B1

nons

yndr

omic

hea

ring

loss

and

dea

fnes

s (8

.6%

) p

heny

lala

nine

hyd

roxy

lase

def

icie

ncy

(6.5

%)

alp

ha th

alas

sem

ia (6

.2%

) c

arni

tine

palm

itoyl

trans

fera

se II

def

icie

ncy

(4.1

%)

Wils

on d

isea

se (4

.0%

) fr

agile

X s

yndr

ome

(3.8

%)

Sm

ith-L

emli-

Opi

tz s

yndr

ome

(3.7

%)

PK

HD

1-re

late

d au

toso

mal

rece

ssiv

e po

lycy

stic

kid

ney

dise

ase

(3.1

%)

Eas

t Asi

an14

924

3367

875.

80%

94.2

0%92

GJB

2-re

late

d D

FNB

1 no

nsyn

drom

ic h

earin

g lo

ss a

nd d

eafn

ess

(33.

5%)

alp

ha th

alas

sem

ia (8

.9%

) K

rabb

e di

seas

e (5

.2%

) P

endr

ed s

yndr

ome

(5.0

%)

Hb

beta

cha

in-r

elat

ed h

emog

lobi

nopa

thy

(4.4

%)

Wils

on d

isea

se (3

.7%

) 2

1-hy

drox

ylas

e-de

ficie

nt c

onge

nita

l adr

enal

hyp

erpl

asia

(3.2

%)

prim

ary

carn

itine

def

icie

ncy

(3.1

%)

phe

nyla

lani

ne h

ydro

xyla

se d

efic

ienc

y (2

.5%

) fr

agile

X s

yndr

ome

(2.3

%)

Kas

eniit

et a

l. S

uppl

emen

tal T

able

sTa

ble

S4

Tabl

e S4

: Car

riers

mis

sed

by e

thni

city

-spe

cific

car

rier s

cree

ning

com

pare

d to

pan

-eth

nic

expa

nded

car

rier s

cree

ning

. Ind

ivid

uals

who

wer

e ca

rrie

rs fo

r m

ultip

le d

isea

ses

wer

e co

unte

d fo

r eac

h di

seas

e.

ethn

icity

carr

iers

id

entif

ied

carr

iers

m

isse

dpa

tient

s te

sted

carr

ier s

ensi

tivity

re

lativ

e to

pan

-et

hnic

EC

Sm

isse

d ca

rrie

rs re

lativ

e to

pan

-eth

nic

ECS

dise

ases

with

m

isse

d ca

rrie

rsto

p di

seas

es w

ith p

ropo

rtio

n of

all

mis

sed

carr

iers

His

pani

c28

619

0666

9013

.00%

87.0

0%87

21-h

ydro

xyla

se-d

efic

ient

con

geni

tal a

dren

al h

yper

plas

ia (1

4.0%

) a

lpha

thal

asse

mia

(10.

4%)

GJB

2-re

late

d D

FNB

1 no

nsyn

drom

ic h

earin

g lo

ss a

nd d

eafn

ess

(9.2

%)

frag

ile X

syn

drom

e (5

.8%

) fa

mili

al M

edite

rran

ean

feve

r (5.

0%)

Hb

beta

cha

in-r

elat

ed h

emog

lobi

nopa

thy

(4.7

%)

phe

nyla

lani

ne h

ydro

xyla

se d

efic

ienc

y (3

.7%

) P

KH

D1-

rela

ted

auto

som

al re

cess

ive

poly

cyst

ic k

idne

y di

seas

e (3

.1%

) c

onge

nita

l dis

orde

r of g

lyco

syla

tion

type

Ia (3

.0%

) S

mith

-Lem

li-O

pitz

syn

drom

e (2

.7%

)

Mid

dle

Eas

tern

281

671

2152

29.5

0%70

.50%

69

fam

ilial

Med

iterr

anea

n fe

ver (

22.5

%)

21-

hydr

oxyl

ase-

defic

ient

con

geni

tal a

dren

al h

yper

plas

ia (1

3.1%

) fr

agile

X s

yndr

ome

(8.3

%)

GJB

2-re

late

d D

FNB

1 no

nsyn

drom

ic h

earin

g lo

ss a

nd d

eafn

ess

(7.2

%)

phe

nyla

lani

ne h

ydro

xyla

se d

efic

ienc

y (6

.6%

) P

KH

D1-

rela

ted

auto

som

al re

cess

ive

poly

cyst

ic k

idne

y di

seas

e (3

.4%

) P

ompe

dis

ease

(2.8

%)

her

edita

ry fr

ucto

se in

tole

ranc

e (2

.7%

) W

ilson

dis

ease

(2.4

%)

incl

usio

n bo

dy m

yopa

thy

2 (2

.2%

)

Mix

ed o

r Oth

er

Cau

casi

an18

2510

585

2863

914

.70%

85.3

0%93

21-h

ydro

xyla

se-d

efic

ient

con

geni

tal a

dren

al h

yper

plas

ia (7

.1%

) G

JB2-

rela

ted

DFN

B1

nons

yndr

omic

hea

ring

loss

and

dea

fnes

s (7

.1%

) fa

mili

al M

edite

rran

ean

feve

r (5.

8%)

frag

ile X

syn

drom

e (5

.2%

) p

heny

lala

nine

hyd

roxy

lase

def

icie

ncy

(5.1

%)

Sm

ith-L

emli-

Opi

tz s

yndr

ome

(4.3

%)

med

ium

cha

in a

cyl-C

oA d

ehyd

roge

nase

def

icie

ncy

(3.7

%)

alp

ha th

alas

sem

ia (3

.3%

) P

ompe

dis

ease

(3.1

%)

con

geni

tal d

isor

der o

f gly

cosy

latio

n ty

pe Ia

(2.8

%)

Kas

eniit

et a

l. S

uppl

emen

tal T

able

sTa

ble

S4

Tabl

e S4

: Car

riers

mis

sed

by e

thni

city

-spe

cific

car

rier s

cree

ning

com

pare

d to

pan

-eth

nic

expa

nded

car

rier s

cree

ning

. Ind

ivid

uals

who

wer

e ca

rrie

rs fo

r m

ultip

le d

isea

ses

wer

e co

unte

d fo

r eac

h di

seas

e.

ethn

icity

carr

iers

id

entif

ied

carr

iers

m

isse

dpa

tient

s te

sted

carr

ier s

ensi

tivity

re

lativ

e to

pan

-et

hnic

EC

Sm

isse

d ca

rrie

rs re

lativ

e to

pan

-eth

nic

ECS

dise

ases

with

m

isse

d ca

rrie

rsto

p di

seas

es w

ith p

ropo

rtio

n of

all

mis

sed

carr

iers

Nor

ther

n E

urop

ean

1495

8110

2131

715

.60%

84.4

0%93

21-h

ydro

xyla

se-d

efic

ient

con

geni

tal a

dren

al h

yper

plas

ia (7

.1%

) G

JB2-

rela

ted

DFN

B1

nons

yndr

omic

hea

ring

loss

and

dea

fnes

s (6

.5%

) p

heny

lala

nine

hyd

roxy

lase

def

icie

ncy

(5.3

%)

frag

ile X

syn

drom

e (5

.1%

) fa

mili

al M

edite

rran

ean

feve

r (5.

0%)

Sm

ith-L

emli-

Opi

tz s

yndr

ome

(4.2

%)

con

geni

tal d

isor

der o

f gly

cosy

latio

n ty

pe Ia

(3.5

%)

med

ium

cha

in a

cyl-C

oA d

ehyd

roge

nase

def

icie

ncy

(3.5

%)

Pom

pe d

isea

se (3

.0%

) P

endr

ed s

yndr

ome

(2.4

%)

Sou

th A

sian

189

1100

4433

14.7

0%85

.30%

80

alph

a th

alas

sem

ia (2

3.3%

) H

b be

ta c

hain

-rel

ated

hem

oglo

bino

path

y (1

2.5%

) G

JB2-

rela

ted

DFN

B1

nons

yndr

omic

hea

ring

loss

and

dea

fnes

s (9

.8%

) 2

1-hy

drox

ylas

e-de

ficie

nt c

onge

nita

l adr

enal

hyp

erpl

asia

(5.5

%)

frag

ile X

syn

drom

e (4

.2%

) fa

mili

al M

edite

rran

ean

feve

r (3.

6%)

Wils

on d

isea

se (3

.4%

) P

endr

ed s

yndr

ome

(3.1

%)

prim

ary

carn

itine

def

icie

ncy

(3.0

%)

med

ium

cha

in a

cyl-C

oA d

ehyd

roge

nase

def

icie

ncy

(1.8

%)

Sou

thea

st A

sian

229

524

1882

30.4

0%69

.60%

69

GJB

2-re

late

d D

FNB

1 no

nsyn

drom

ic h

earin

g lo

ss a

nd d

eafn

ess

(49.

4%)

Pen

dred

syn

drom

e (5

.0%

) K

rabb

e di

seas

e (3

.8%

) p

rimar

y ca

rniti

ne d

efic

ienc

y (3

.8%

) 2

1-hy

drox

ylas

e-de

ficie

nt c

onge

nita

l adr

enal

hyp

erpl

asia

(3.4

%)

pol

ygla

ndul

ar a

utoi

mm

une

synd

rom

e ty

pe 1

(2.5

%)

frag

ile X

syn

drom

e (2

.1%

) p

heny

lala

nine

hyd

roxy

lase

def

icie

ncy

(2.1

%)

Wils

on d

isea

se (1

.7%

) P

ompe

dis

ease

(1.5

%)

Kas

eniit

et a

l. S

uppl

emen

tal T

able

sTa

ble

S4

Tabl

e S4

: Car

riers

mis

sed

by e

thni

city

-spe

cific

car

rier s

cree

ning

com

pare

d to

pan

-eth

nic

expa

nded

car

rier s

cree

ning

. Ind

ivid

uals

who

wer

e ca

rrie

rs fo

r m

ultip

le d

isea

ses

wer

e co

unte

d fo

r eac

h di

seas

e.

ethn

icity

carr

iers

id

entif

ied

carr

iers

m

isse

dpa

tient

s te

sted

carr

ier s

ensi

tivity

re

lativ

e to

pan

-et

hnic

EC

Sm

isse

d ca

rrie

rs re

lativ

e to

pan

-eth

nic

ECS

dise

ases

with

m

isse

d ca

rrie

rsto

p di

seas

es w

ith p

ropo

rtio

n of

all

mis

sed

carr

iers

Sou

ther

n E

urop

ean

295

990

2812

23.0

0%77

.00%

84

fam

ilial

Med

iterr

anea

n fe

ver (

10.2

%)

21-

hydr

oxyl

ase-

defic

ient

con

geni

tal a

dren

al h

yper

plas

ia (1

0.0%

) G

JB2-

rela

ted

DFN

B1

nons

yndr

omic

hea

ring

loss

and

dea

fnes

s (7

.8%

) p

heny

lala

nine

hyd

roxy

lase

def

icie

ncy

(6.8

%)

frag

ile X

syn

drom

e (6

.2%

) S

mith

-Lem

li-O

pitz

syn

drom

e (4

.1%

) P

ompe

dis

ease

(3.6

%)

her

edita

ry fr

ucto

se in

tole

ranc

e (3

.5%

) c

onge

nita

l dis

orde

r of g

lyco

syla

tion

type

Ia (3

.2%

) W

ilson

dis

ease

(2.3

%)

all

9653

3245

691

395

22.9

0%77

.10%

94

GJB

2-re

late

d D

FNB

1 no

nsyn

drom

ic h

earin

g lo

ss a

nd d

eafn

ess

(10.

0%)

21-

hydr

oxyl

ase-

defic

ient

con

geni

tal a

dren

al h

yper

plas

ia (8

.9%

) fa

mili

al M

edite

rran

ean

feve

r (7.

6%)

phe

nyla

lani

ne h

ydro

xyla

se d

efic

ienc

y (4

.9%

) fr

agile

X s

yndr

ome

(4.9

%)

alp

ha th

alas

sem

ia (4

.6%

) S

mith

-Lem

li-O

pitz

syn

drom

e (3

.5%

) W

ilson

dis

ease

(2.7

%)

con

geni

tal d

isor

der o

f gly

cosy

latio

n ty

pe Ia

(2.6

%)

Pom

pe d

isea

se (2

.6%

)

Table S5 is included as a supplemental Excel file on the GIM website.