Discovery of Essential Human Genes by Querying a Large Clinical Cohort
with DNA Copy Number Loss with Available Literature and Databases
Rachel D. Burnside1, Inder Gadi1, Vik Jaswaney1, Andrea Penton1, Karen Phillips1, Venketeswara Potluri2, Hiba Risheg3,
Stuart Schwartz1, Justin Schleede1, James Tepperberg1, Romela Pasion1, Huong Cabral1, Laura Kline1, Kacie Riley1, Sharon Molinari1,
Margriet Johanson1, Jenny Shafer1, Bing Huang4, Jay Leonard4, Judith Knops4, Naga Guruju4, Hongyan Xie4, Sekhon Gurbax4, Peter Papenhausen1
Laboratory Corporation of America Holdings, Center for Molecular Biology and Pathology, Research Triangle Park, NC, 2LabCorp, Houston, TX, 3LabCorp/Dynacare, Seattle, WA, 4Integrated Genetics, Santa Fe, NM
1
INTRODUCTION
There are an estimated 25,000 genes in the human genome, with around
2% genes transcribed to mRNA. Even though many genes and regulatory
elements or regions have been identified in numerous studies, the function
of many genes remains unknown, complicating interpretation of CNVs
in clinical microarray studies. Essential genes are defined as those which
are required for viability of the cells during embryonic and later fetal
development. We propose that there are regions of the autosomal genome
in which copy number loss of essential genes and/or regulatory elements
in those regions is not tolerated and will not be observed in live born or
possibly even in recognized pregnancies. While it is possible that very small
copy number losses exist in our total patient cohort below the resolution
and/or reporting criteria for SNP microarrays, or that are not observed by
this lab, we propose that the size of our abnormal cohort and the database
and literature searches will provide sufficient data to yield informative results
with respect to regions of the genome that are not observed as deleted.
From August 2008-December 2015, we have performed ~100,000 postnatal
SNP microarrays. From those for which a copy number change was
reported, ~11,000 (11%) had a non-mosaic deletion in an autosome.
We investigated what regions of the autosomal genome were NOT
represented in this cohort to narrow down areas where essential genes
may be present. This initial investigation yielded 59 regions covering all
autosomes with the exception of chromosome 21. These regions were then
refined or eliminated based on further database searches to arrive at a list
of genes for which no copy number losses or loss-of-function mutations
have been reported in humans or animal model organisms. We propose
that at least some of these genes may play an essential role in animal
development and that haploinsufficiency, either by gene loss or disruption
or loss-of-function mutations is not well tolerated.
METHODS
From our cohort of ~100,000
postnatal microarray cases,
there were ~11,000 non-mosaic
deletions reported since
August 2008. These were sorted
by chromosome and linear
position, and then analyzed for
regions on each autosome
that were not deleted. These
intervals were then compared
against non-mosaic deletion
entries in DECIPHER®
[GenomeDx Biosciences, Inc.]
to eliminate intervals of overlap
or refine or divide intervals into
smaller segments. This process
was repeated again using
ISCA/ClinGen database
entries, and then again using
DGV large deletion variants
(Figure 1). This initial process
yielded 41 regions on
13 chromosomes. The
individual genes in these
regions were again queried
in DGV to eliminate those
genes with smaller deletion
variants that overlapped
coding regions of the genes,
with the assumption that any
coding region deletions would
affect the endogenous
function of the gene. This
process left 36 regions on
13 chromosomes:
32 genes in 9 intervalson Chr 1
7 genes in 2 intervalson Chr 3
8 genes in 3 intervalson Chr 4
4 genes in 2 intervalson Chr 5
8 genes in 1 interval on Chr 6
4 genes in 2 intervalson Chr 9
3 genes in 1 interval on Chr 10
12 genes in 4 intervalson Chr 11
3 genes in 1 interval on Chr 14
11 genes in 2 intervalson Chr 15
2 genes in 1 interval on Chr 18
35 genes in 6 intervalson Chr 19
6 genes in 2 intervalson Chr 20
&(.-2. 3'&-.,1/.13
;.71+3.+3
P
C+(--
+1&81(-32
RESULTS
All regions on chromosomes
2, 7, 12, 13, 16, 17, 21, and 22
were shown to be deleted
in at least one individual
in at least one database.
Chromosomes 5 and 8
had regions around the
centromere which no
database showed deletion,
but there were also no genes
in those pericentromeric
regions.
After eliminating genes
through the process described
in Figure 1, 65 genes on
12 chromosomes remained
(Table 1). Perhaps not
surprisingly, chromosomes 1
and 19 had the most
remaining genes. The function
of 25 genes is unknown
(light blue), and 7 of the
unknown genes are proposed
as non-coding RNAs.
5 genes appear to have
an abnormal developmental
or lethal haploinsufficient
phenotype (orange,
dark=lethal, light=abnormal),
and may be promising for
more research.
14 genes in 6 intervalson Chr 1
4 genes in 1 interval on Chr 3
5 genes in 2 intervals on Chr 4
4 genes in 1 interval on Chr 6
1 gene in 1 interval on Chr 9
2 genes in 1 interval on Chr 10
4 genes in 2 intervals on Chr 11
1 gene in 1 interval on Chr 14
5 genes in 2 intervals on Chr 15
1 gene in 1 interval on Chr 18
20 g
enes in 4 intervals on Chr 19
TA
VA
WA
YA
\A
TSA
TTA
TWA
TXA
T[A
T\A
USA
9;1(.2.,+/1.3(-TVG*
>92`31-2/.14-&
TVH@(.2.,2.-2(23. 2,++WS
T277-(3G*Y??
277-(3-+1&YS277-(3B.&3'1
[H@'(2&--.2.,/.--3
3'2277-(321.,/.2. W
=*+'+(* ,(+;,,1X@'
<1&-14-& ,(+;,,1WG*
@@D
H@+.-&(-&3.3'+(7,GD
3;/H/--3+4-27/1 ,(+;
=49X-42-2T
*+'D1/3/1.3(- ,(+;(21-3+; .7-
-9*(-. 4-D(-(-&/1.3(-B
3(2
'131(<;3-,+;11-&,.4 2. .73XS,(-.(2B18(.72237;2'.9
3'3,.23,,12. 3'*+'D1/3 ,(+;
91;3.2*+3+/1.3(-2(,/+(3(-81(.72
++7+1/1.222?27'24-;3.2*+3.-
(-314.-?;3./+2,(2072314.-. 31-21(/4.- 3.12-++,.1/'.+.&;I
A >&(:::'1.,.2.,Y./-
1(-& 1,UUU
TWYZUWTSJ
9*(-2-'.1(-&/1.3(-T
G*UT@WUH@'(2&-
-.2/1.3(-3'3(2'(&'+;2(,(+13.3'
,.72D/--3/1.3(-*(-2
-'.1(-&/1.3(-WU*B',.72/1.3(-
'2- .7-3.+.+(<9(3'3'.+&(-
117(3D/--3/1.3(-*(-2
+/'
3.3'.+&((-,.723232B
3(23'.7&'33.
/+;1.+(-&1,++8+./,-3B
1-21(/381(-32-.(-&(!1-3(2. .1,2
'8- .7- .13'(2&-BI/1.8(; 98&(?>'1.,.2.,TS./-
1(-& 1,ZY
0?3USS[J
2/(2-//1.:(,3+;[S2317371++;
. 87.+12GD2H?
,7+4277-(3-<;,3'3,(32
(24-3/1.3(-2B'(2&--.2
1(.2.,+/1.3(-3'3(2.,/.--3. 3' (("4.-. 7*1;.4(-31++7+1
WS277-(3B'/1.3(-+.-&23.3'TX .1&-++2BD2/--3.1&-++
,(+;. 1(.2.,+/1.3(-2B
3(2+.3(- (("4.-(2-221; .127'
3';3./+2,B'/1.3(-'2-2'.9- (-31++7+1/1.2222/1.3(-2.14-&?
<;,.&-484.-?1/3.1D,(3
3.(-3.3'XB[1(-13B'&-
-.;3.2(2?-2;-/482(+/1.3.-
/1.73. 3'B.+(.13'.+.&G1(.2.,+
/1.3(-TXH 7-4.-231+;23/2(-
&1(-3&-14.-BD2(2
.,/.2. ;3.2.+(T.,(--
1(.2.,22,+;B'(2&-(2.D
;+.';1.+2
31-21(9(3'39.TW2,++-7+.+131-2,,1-S.,(-B'T
*1&7+3.1G*?
&-2?9'('1+.3(-(323'(1-"%' .,(-.-2(232. 3'1-3'1
:3;+D.
277-(32?39.277-(32/+723'????2TY\VV?VXH@;+.';1.+2
(-31.-2B2(23;/(+ .1&-2-.(-&
1(.2.,+/1.3(-2?3'11,7+4/+
-277-(32B'T.,(-.-3(-2 *1&7+3.1;/1.3(-(-23.- ;+31-2 12UG*
3'3+;42(3B'S.,(-
,(32331';1.(./31(-(-'((4.-. H@'-./1.3(-
/1.22/27.&-2. 3'(2&-
(2/123'1.7&'3'&-.,BI/1.8(; .-2(232. "8(!1-3277-(32A??N? ;+.';1.+2
B'1&7+3.1;
3+;<23'+2323/. 3'
O?-B(4.-+(2. .1,2. ,-;. /1.3(-??.-2(232. '.,.(,1B ,(3.'.-1(+ 6;(3D
0?7+USS[J@+(2'31.<;&.72 .1
3(2/.237+33'3,;/+;1.+.:(4.-2/(1+B-+(*,.23
K+LGUHVUGTH'8,(7,(-73 3'T-S277-(3/1.3(-21
/'-.3;/B.,,.-31(32. 3'(-73
-.;,7+4/+&-2.1+31-48+; (-1&7+4-&/'-;++-(-,3.+(2,(- ,(3.'.-1(+,31(:/1.3(-2?(3
3'+(81-(-3'/1.74.-. (.&-( .-3(-2-.-D+8+,(-.D
/'-.3;/12'.13-3'(-1(23+2?2+.9 2/+(31-21(/381(-32B'(2&-
8+./,-3?-122(8+3'+(3;B
A -.23'T.,(-277-(3/1.3(-B ,(--71.31-2,(612--(31(.:(B 31,(-+31&4-&2(&-+B
I/1.8(; 0?7+USS[J
I/1.8(; 0?7+USS[J
I/1.8(; 0?7+USS[J
[ZUXUVX
9:< -2(-3
TUWG*DUWH@
-2(-21;23(-D1('
:,,1-22.(31(-&D 4.-(/.+;//423'31
(,/.13-3(-3''.23
D3;/"-&1UG*UWS?
(,,7-.+.&(12/.-23.
D
?TZUH@U(2
(-8(-&,(1..1&-(2,2B'(2
,,1. 3' ,(+;. ,,1-D -4,(1.(+/1.3(-(2
.7-V7(07(4-+(&22GYBVBUBT\HB
213-(2,,1. -<;,27(07(4-G2
3'3 -2(-/1.3(-
T\TVV\H3.31&3+;2(-2(-272313/1.3(-2? ,(+;B3 -2(-&-21
3'1;2(&-+(-&3'(182(7+131-2/.13
.7-(-281++72312
39-,,1-.,/13,-32BU 3'1.7&'.733'&-.,?9(3'
172271 7,7+4.-. 281+
3'(2&-,//(-&3.+7231
&+;./1.3(-2-//123.1&7+31+; 3US0TTBTB'-.
-.2.,D3.D31-2D.+&(-39.1*GH
/1.3(-,;2183.-'-
31#*(-&G133+B?USSWI7
(--3(,,7-(3;(-3'
TWZUUUYYJ@*,713+B?USSXI7 /1.233BI/1.8(; 0?
TXY[\W\\JHBI27//+(;
?1USTSJ
.8USTWJ
A1(.2.,+/1.3(-\G*\@
DDTYH@(.2.,2.-2(23. 2,++WS
277-(3-+1&YS277-(3B.&3'13'2
277-(321.,/.2. W2/(2-
//1.:(,3+;[S2317371++;(24-3/1.3(-2B
9 1&,-3. &1/3.1
G*
'(2&--.21(.2.,+/1.3(-3'3(2
YW@
H@'1(24-3?73+.2+;1+3
.,/.--3. 3'YS277-(3B'/1.3(-
+222. 1/3.123'3(-3'/.14.-. &'8
+.-&23.3'Y ,(+;. 1(.2.,+/1.3(-2B
-(-4"G&,,
?
-
HB'&,,
3(2+.3(-3';3./+2,B2(23;/(+ .1
,(+;.-2(232. 3'1+.2+;1+3&-231,? ;=VD.,(-(-(-&/1.3(-X&-2-.(-&1(.2.,+/1.3(-2?3'11
G22.(3HG*@VDXH@ ,7+4/+/1.22/27.&-2. 3'(2&-
?-B'(2&--.23'+.9#-(3;
&,,
1/3.13'3,;/+;-(,/.13-31.+ .- .+(,,7-.;3.',(231;-++
(2/123'1.7&'3'&-.,B+31-48
2/+((-&127+32(-,7+4/+31-21(/381(-32B
14.-4.-237(2(-(33'3(2
(-'7,.1+(,,7-12/.-2B+31-48+;2/+(
22.(39(3',(3.'.-1(-(2D7-D I/1.8(; 0?USTYJ@'31.<;&.72
31-21(/381(-32-.(-&(!1-3(2. .1,2'8
-21( .13'(2&-BI/1.8(; 0?3 31,(-+*(-2GHD(-314-&/1.3(-I
A ,73-31.2./'(+:'((3(-73/'-.3;/
TUTYZS[[J
USTTJ
- ,+212,(231(+I
A[YZY[[UJ
>&(@A'1.,.2.,Y./-
1(-& 1,[\G*H@G+(.4
3+H1/.133'3Y.1 [\?9'('-.2.-
2.+7+-39.3;/
,,1-/1.3(-2
3'3 7-4.-2'(23.-3;+22GH
-'-12BI
UVWYSVV[JBG(73+H
27&&2323'33'/1.3(-(2-
(,/.13-31&7+3.1. (,,7--
(-$,,3.1;12/.-22(-3''7,-(19;
/(3'+(7,BI
AUYWYSW[ZJ
9-7+.+1-.(+D.;
/'.2/'./1.3(-TG*TVS@
TVS@TWS@XTVH@
.//TWS22.(329(3'2,++-7+.+1
23.'/1.-/1D1/1.22(-&-
1(.2.,22,+;@'-.3;/(:/122(.-
.11+39(3'3'/1-3+.22. .//TWS
31-21(/32Ab.1aXS_+.22.11+39(3'
+18+-/7/++3'+(3;?(217/3-7+1
23173712?-(-2.,22,+-.4
37,.12I
ATZV\UXS\J
<+3D+(*WG1.2./'(+H
G*'+3UH@'(2&-(2'.,.+.&
98A31-2,,1-/1.3(-
TS\
98899TSS+(7,(-(-&/1.3(-TT
G*ZS@TSS@DDWVH@'/1.3(-
-.;3'(2&-(2,,1. 3'TSS ,(+;. /1.3(-2.-3(-(-&UD'-+(7,D(-(-&,.4 2B
TSS/1.3(-21+.+(<(-3';3./+2,-C.1
-7+72. 9(1-&. ++2?-(-8.+8(-3'
1&7+4.-. -7,1. ++7+1/1.22227'2++
;+/1.&122(.--(!1-44.-BTSS&-2
(-+73+23TV,,129'('1+.32
+7231.-'1.,.2.,T0UTB'(2/1.3(-,; 7-4.-
;<49VW-42-2T
(-,.4+(3;?(-82(.-?-377+(-/.+;,1(<4.-B
;=49VX-42-2T G'3.'H
I/1.8(; 0?7+USS[J
9/,3';+31-2 12T
G*1T@'1T@U@
SS[UH@'1T3+;<22/("
,3';+4.-. 3'UNDD1(.2. 3'"123
-7+.4. //31-21(/3I
A
USZTVVXYJ
9G-
HD+(*D(-(-&T
G*A?H@'
9;:31-2,,1-
/1.3(-TVUG*?XTH@
'(2&--.2/1.3(-3'3(2'(&'+;
2(,(+13.3'131/Z[D(-(-&/1.3(-
GHB+31-48+;2/+(31-21(/381(-32
-.(-&(!1-3(2. .1,2'8-
21(BI/1.8(; 0?7+USS[J
. 3'1.2./'(++3&-B'+3
&- ,(+;-.2.3'+(&-23'3
1'131(<;.,(-?
1/32?-31-2,,1-.,(-B
I/1.8(; 0?7+USS[J@
/+.(-27#(-;. +3D+(*W+(&-G(-
,(H127+32(-,1;.-(+3'+(3;73.
,).1 32(-131(+-827+1
8+./,-3BI
ATXXUSVYZJ
3'/12-3237;?9 .7-3'3
4832X27 ,(+;/1.3(-2(-
22;2(-8(31.BI
AUUU\T\\TJ
/1.3(--.;3'(2&-(2
2-,,1. 3'
D+(*D(-(-&/1.3(-
,(+;B'-./1.3(-(2
:/122(--.3'+(+++2?
9'1(3/1.,.32
1.1&-(<4.-. 3'4-
;3.2*+3.--,.1/'.+.&(+
'-&2(-3'++2BI/1.8(
; 0?7+USS[J
:.(+D.(+&+73,31('
/1.3(-UG*YWVYY\H
888:@+.-&
(-31&-(-.-D/1.3(-
.(-&U[G*
US.1 \V@SSSU[@
TS\VTUBYH
2-(-313.1+(*@
-
9'&+733'(.-D2/("
&,,D&+73,;+;+.31-2 12
T@'T(2,,,+(-/1././4
/1.3(-. 7-*-.9- 7-4.-(-7
71(-&-./+2,(147+7,23122B
2'.972(-&(-8(8.237(2--.8+(-
8(31.22;23'33'' ,(+;. /1.3(-2 7-4.-2>D&+73,;+
;+.31-2 1224-&2/("++;3.
&1&+733'(.-I
AUVSZSVYWJ
9:,(3.'.-1(+1(.2.,+
/1.3(-TUG*DTU?D
TU?TU?TU?TUH@
:=,(3.'.-1(+1(.2.,+
/1.3(-UXG*UX@DUXH@ ;<1(.2.,+/1.3(-VWG*
,,+(-,(3.'.-1(+1(.2.,+/1.3(-2 VWH@(.2.,2?3'.1&-++23'33+;<
1-.;-7+1&-2-'+/(-
/1.3(-2;-3'2(2?.-2(23. 2,++WS277-(3
/1.3(-2;-3'2(29(3'(-3',(3.'.-1(.-B
-+1&YS277-(3B.&3'13'2277-(32
1.,/.2. W2/(2-
(3.'.-1(+1(.2.,2G,(3.1(.2.,2H
.-2(23. 2,++U[277-(3-+1&V\ //1.:(,3+;[S2317371++;(24-3/1.3(-2B
277-(3B';'8-24,3ZX_/1.3(-3. '(2&--.21(.2.,+/1.3(-3'3(2
1.,/.2(4.-.,/13./1.*1;.4
.,/.--3. 3'YS277-(3B'/1.3(-
931('.';+(-+(*TG*T@
1(.2.,2?9'13'(214.(21812B-.3'1 +.-&23.3'VW ,(+;. 1(.2.,+/1.3(-2B
TSSTZH@'(2&-+.-&23.3'TSS 72D3;/ (!1-39-,,,+(-,(3.1(.2.,2 3(2+.3(-3';3./+2,B'(2&-.1(&(-++;
923'.7&'33.+.33TZ0UT?73(3'2
/1.3(-GH&- ,(+;?-(2+.3(-+7231. -/1.*1;.41(.2.,2(23'33'+61
&-2.-'1.,.2.,T0UTB81+,,12. .-3(-X1B,.-&(!1-32/(2?3' -,//3.W0B81:/122(.-. 3'(2&-
'2-.218(-2.,-1++2B
3'(2 ,(+;'8-(,/+(3(-3'8+./,-3. /1.3(-2.,/1(2(-&3',(3.1(.2.,(!1
&13+;(-207-?-2.,4,2(-
+31-482/+((-&127+32(-,7+4/+31-21(/3
.,/+:2*(-(2.112B'(2&-(28.+74.-1(+;
81(-32?++-.(-&3'2,(2. .1,B2(2
.-218@(32:/122(.-//123.'(1D2/("
(.',(+/1./142?9'('/18-322;
1.&-(4.-;207-'.,.+.&;B'(2&- 3;/(+ .1&-2-.(-&1(.2.,+/1.3(-2?
-2/4++;1231(39(3'(-3'(23+(--11..3
9>?.(+D.(+.,(-
2'3'. 3''(1 .++(+B
33'72,;'8-(,/.13-3-.2U[277-(3/1.3(-B/27.&- 3'11,7+4/+/1.22/27.&-2. .-3(-(-&TYZG*UYX@
3'(2&-(2/123'1.7&'3'&-.,B
1.+(-'(1,.1/'.&-2(2BI/1.8(; 0?7& .112/.-(-&3.3'(2&-(2 .7-.-
'1.,.2.,WBI/1.8(; 0?7+USS[J I/1.8(; 0?USTYJ
Y.1 TU\H
USTVJ
<1(.2.,+/1.3(-WG*
WH@(.2.,2.-2(23. 2,++WS
9=;2.+7311(1 ,(+;TX
G.+(&.//431-2/.131H?,,1
VG*?U?VH@,,+(-
,,12. 3'/1.3.-D.7/+.+(&.//4
31-2/.131 ,(+;GTXH1(-3&1+
,,1-/1.3(-23'3,(33'++7+1
7/3*. (C31(//42-//4D+(*
17&2I
AUVXSY[ZWJ
277-(3-+1&YS277-(3B'(2&-
-.21(.2.,+/1.3(-3'3(2
.,/.--3. 3'YS277-(3B'
/1.3(-+.-&23.3'W ,(+;. 1(.2.,+/1.3(-2B
3(2+.3(-3'
;3./+2,B2(23;/(+ .1&-2-.(-&
1(.2.,+/1.3(-2?3'11,7+4/+
/1.22/27.&-2. 3'(2&-
(2/123'1.7&'3'&-.,BI/1.8(
; 0?7+USS[J
,,+(-,(3.'.-1(+1(.2.,+/1.3(-2
1-.;-7+1&-2-'+/(-
/1.3(-2;-3'2(29(3'(-3',(3.'.-1(.-B
(3.'.-1(+1(.2.,2G,(3.1(.2.,2H
.-2(23. 2,++U[277-(3-+1&V\
277-(3B'(2&--.2U[277-(3
/1.3(-3'3+.-&23.3'1(.2.,+/1.3(-
TU ,(+;B'-./1.3(-(2*;
.,/.--3. 3'1(.2.,+2,++277-(3-
.-31.+23'.(-&"+(3;-272/4(+(3;
3.,(-.&+;.2(-4(.42B'&- .1
,(3.'.-1(+21;+D32;-3'32(2+.3
7/231,-)-33.3'(2&-?-.3'
&-21/.22(+-(32 .13'
73.2.,+.,(--3 -22&-GWHB
G+3'.7&'1&7+3.1;,734.-2!4-&
(3'1&-.7+24++(-8.+8(-3'
/'-.3;/?2317371+&-,734.-2
!4-&.1TU-:+7
1.,.-2(14.-23'72. WD
+(-* -22?3+23(-3' ,(+(2
(-4"3'72 1BI
ATTVTZVYVJHB/+(
81(-323'3(!1(-3'XN'8-
.7- .13'(2&-@++3'181(-32-.
3'2,/1.3(-BI/1.8(; 0?7+
USS[J
+32+(*G*?H@
9;D.:TVG*
TU@.:DTVH@'(2
&--.2,,1. 3'GD1+3D
.:H ,(+;. 31-21(/4.- 3.12(-8.+8(-3'
1&7+4.-. ,1;.-(8+./,-3-(-3'
31,(-4.-. ++ 3B'-./1.3(-,;3
231-21(/4.-+1&7+3.1%1 .1,(-&/1.3(-
.,/+:9(3'.3'1/1.3(-2B
3'2+2.-
31,(-3.3;/DT(3273.-4&-?+2.
*-.9-2(2+3++-4.;TUBI/1.8(; 0?7+
USS[J
'(2&--.2,,1. ,(+;T
&+;.2(22B+;.2(221-<;,2
3'3';1.+;<&+;.2((.-2-1
+22("(-3. ,(+(22.-/1(,1;
,(-.(207-B.23,,12. ,(+;T'839..-218&+73,((
12(72?9'('1107(1 .1-<;,4
48(3;B',.72.13'.+.&. 3'(2
/1.3(-'2-'131(<-'2
.,(-2317371. -D31,(-+2(&-+
//4?&+;.2(2.,(-?
31-2,,1-.,(-?-2'.13
;3./+2,(3(+B
3+*2.-. 3'
.-218&+73,((12(72
(,/.13-3 .13+;2(2?-(32 7-4.-
1,(-23.31,(-G
A
TUS[WX[UHB+31-482/+((-&127+32(-
,7+4/+31-21(/381(-32BI/1.8(;
0?7-USTVJ@(2.-(2. .1,. 3'+.3'. ,(+;. 3.123'3
..1(-3(-314.-39-(!1-3
+(&-2-3'1/3.1BI
A
UUSUS\VUJ
.+(&.2'1;+31-2 12
.,/+:277-(3G-.-D3+;4HG*
UH@(-3'(-4"4.-. CU2
-.8+277-(3. ,,,+(-
.+(&.2'1;+31-2 12;'(3-(3+B?
+(6+'2-31,(-.733'
/';2(.+.&(+ 7-4.-. CUB71237;
G'-3+H(-4"2/.3-4+1.+. C
UA1&7+3.1C,(3.1. ,,,+(-'3
2'.*12/.-2I
AUWZXTV[V?TX[VX[[ZJ
:?D.:/1.3(-UZG*X?
:UZH@,12. 3'D.:/1.3(- ,(+;?
27'2UZ?1'131(<;-
//1.:(,3+;WSD,(-.(D.:,.4 B
.,/+:2? .1,;TG
YSTWVWH?
7++(-G2T@
YSVTVWH?-D.:
/1.3(-2?32/1.3(-D7(07(4-+(&22BD.:
/1.3(-2(-3139(3'T3'1.7&'3'.:?
-3';(-3139(3'7(07(4-4.-31&32
3'1.7&'.3'1/1.3(-(-314.-.,(-2G(-
3+B?USSWI7TXXUSUZZJHBI27//+(;
?1USS[J@D.:/1.3(-231,(-
3'2723132/("(42. 7(07(4-
+(&22B,.-&3'2?2VCXCUZ
1.&-(<23'D&+;-2. &+;./1.3(-2
I
AUYWYSYTTJ
9T'.,.+.&? TC
/.+;,12
.,/+:.,/.--3
G*UVTW\FT?UH@'(2&--.2
277-(3. 3'/.+;,1222.(3 3.1
GTH.,/+:B'T.,/+:(-3132
9(3'/.+;,12
-/+;21.+(-
31-21(/4.-+.-&4.-29++2'(23.-
,.("4.-2(-+7(-&7(07(3;+4.--
,3';+4.-B+31-48+;2/+(31-21(/3
81(-32-.(-&,7+4/+(2. .1,2'8-
.218 .13'(2&-BI/1.8(; 0?
USTUJ@++'7,-1+3237(21(-
8(31.?-,.2311+33.-1B
88>:@+.-&(-31&-(-.-D/1.3(-
.(-&YU[
:+7(-1('1/3-71.-+UG*
T@X@T@
ZH@'/1.3(-
-.;3'(2&-+.-&23.3'+7(-D1('1/3
27/1 ,(+;B'(2&-92 .7-3.,/+("-
.81:/122(-,+(&--3&+(.,2B'-.
/1.3(-'2'.,.+.&;9(3'.3'1/1.3(-23'3 7-4.-
2++D'2(.-,.+7+2.122(&-+31-274.-
1/3.12-(2-(3 .13'31&3&-(-3'
T0VUBT,/+(.-(-,+(&--3&+(.,2B9.
+31-48+;2/+(31-21(/381(-32-.(-&3'
2,/1.3(-'8-21( .13'(2&-B
I/1.8(; 0?7+USS[J
:A,(3.1.,/+:277-(3
U\G*
H@U\(2277-(3. 3'
(3.1.,/+:?,7+4/1.3(-.483.1
. 31-21(/4.-3'3(-31329(3'D
.7-31-21(/4.-+483.12?
/.+;,12
G2
T[SYYSH?-&-1+
(-(44.- 3.12G3.3+B?USSVI7
TWXZYTY[JHBI27//+(;
?7&USS\J
:7*1;.431-2+4.-(-(44.- 3.1
UG*@XYH@'(2&--.2
31-2+4.-(-(44.- 3.1(-8.+8(-3'117(3,-3
-+(81;. ,(-.;+D323.3'D2(3. 3'
7*1;.41(.2.,(-D(-/--3,--1B'(2
&-92/18(.72+;1 113.2+(&4-?73(2-.9
*-.9-3.+.+(<3.3';3./+2,-+.+(<-
7-4.-9(3'31-2+4.- 3.12B7+4/+31-21(/3
81(-32-.(-&(!1-3(2. .1,2'8- .7-
.13'(2&-BI/1.8(; 0?-USTTJ
.12,++1+4.-81(-32
3'3.,/+3+;.81+/&-
.1.81:.-2. 3'&-
=<><(-"-&1/1.3(-XWYG*
W\H
?@8<(-"-&1/1.3(-Z[S
G*ZZ\H
9&(99>'1.,.2.,T./-1(-&
1,TTYG*H
9'31.&-.72-7+1
1(.-7+./1.3(-D+(*TG*TD
X?TX?TH@'(2&-
9T7(07(4-2G*[@
U@S\[email protected](-7(07(4-4.-.-31.+2
,(-(-&&-2'8-.+4.-
81(-32.1(-31.-(+4.-
81(-32.-+;
7 .1*C.,.+2G3.+(,(-38(+
- 14+'31.<;&.32H?.3'1(-(8(7+2
1/.139(3'+4.-.1122(8(22
G3.+(,(-311(1/1-32H
-323.+(,(-3
/27.&-2
Figure 1. Flowchart
of databases used
to eliminate regions/
genes of the autosomal
genome for which
deletions have been
observed.
Each gene was then queried
in PubMed to eliminate those
genes for which human or
mammalian model organisms
were reported to either have
deletion or loss-of-function
mutation in the primary literature.
Genes were also queried in the NCBI Gene database to identify and
eliminate pseudogenes. The remaining genes included provisional,
reviewed, and validated genes and are shown in Table 1.
ONLINE RESOURCES/DATABASES:
DECIPHER®: https://decipher.sanger.ac.uk/
ISCA/CLINGEN:https://www.clinicalgenome.org/tools-resources/clingen-tools-and-work-products/
http://dbsearch.clinicalgenome.org/search/
DGV: http://dgv.tcag.ca/dgv/app/home
NCBI Gene:http://www.ncbi.nlm.nih.gov/gene/
Table 1. Genes that
have not been reported
with deletions in human
subjects. Light blue genes
are validated or reviewed
genes for which there is no
known function. Orange
genes are those for which
studies describe either
haploinsufficient lethality
(dark orange) or a severe
abnormal haploinsufficient
phenotype (lighter orange)
in an animal model
organism. All information
noted for genes is taken
from the NCBI Gene
database and/or noted
PMID articles.
-.2-7+1D(-(-&/1.3(-. 3'
'31.&-.72-7+11(.-7+./1.3(-
G'-H ,(+;B'(2/1.3(-(-22/("++;
3.-.8(172TDXX*.-./1.3(-B
3,;
/+;-(,/.13-31.+(--7+.;3./+2,(
31-2/.13?-(32 7-4.-(2,.7+3
;TDXX*(--.8(172D(- 3++2B
9.31-21(/381(-32-.(-&(!1-3
(2. .1,2'8- .7- .13'(2&-B
(4.-+81(-32'8+2.- .7-?73
3'(1 7++D+-&3'-3712'8-.3-
31,(-BI/1.8(; 0?7+USS[J
,-;(-31++7+1/1.222?(-+7(-&++;+
/1.&122(.-?31-21(/4.-+484.-?-2(&-+
31-274.-B'(2;-,(/1.22?(-8.+8(-&7(07(4-
.-)7&4-&-<;,2-7(07(4-4-&-<;,2?
2-1,.827(07(4-B7(07(4-4-&-<;,2
1;23(-/1.3223'32/("++;+87(07(4-
1.,7(07(4-D.-)7&3/1.3(-2723132B'
/1.3(--.;3'(2&-+.-&23.
27 ,(+;'131(<;-.81(-37,.1GH
.,(-B+31-482/+((-&127+32(-,7+4/+
31-21(/381(-32BI/1.8(; 0?-USTVJ
<.,/+,-3.,/.--3W(-(-&
/1.3(-?3G*WH@'(2&--.2
,,1. 27/1 ,(+;. /1.3(-2.,/.2
/1.,(--3+;. 3-,+;11;2'.13.-2-272
1/32. //1.:(,3+;YS,(-.(2B2(-&+?
7-(073D'(--.;3'(2&-22,+29(3'
28-(-4++/'D'(-2(-3.3'/1.,(--3
(2. .1,. WD(-(-&/1.3(-?,7+4,1(/1.3(-
3'3.-31.+2484.-. 3'.,/+,-32
3'1.7&'3'+22(+/3'9;BWD(-(-&/1.3(-'2
1&7+3.1;1.+(-3'.&7+4.-2;23,+2.?
,(33'1.7&'3'3D'(-(-(-&. /1.3(-?
8(3,(-D/--3/1.3(-3'321822. 3.1
. 483/1.3(-B'&-2-.(-&.3'+/'
-3'(-21+.3)-33.'.3'1.-
'7,-'1.,.2.,T(-3'1&7+3.1. .,/+,-3
484.-&-+7231B+31-482/+((-&&(821(23.
,7+4/+31-21(/381(-32BI/1.8(; 0?7+
USS[J
=?=<(-"-&1/1.3(-XZX
/'.2/'.+(/2U(-'((3.1
-YC.,(-.-3(-(-&
<49W-42-2T
G*T.1 TVVH
<.,(-.-3(-(-&WG*
W[VVWSWS\@TVSST[TT(*H@ 7-4.-
7-*-.9-?73 .7-(-3'-7+72(-++/'22. 3'
++;+-(2.-2181.22281+2/(2I
TYXWYVVTJ
:::<(-"-&1/1.3(-UUU
9+;2./'.2/'4;+&+;1.+
;+31-2 12TG*[@VW@
VWTH@;+D.A+;2./'.2/'4;+&+;1.+GH
;+31-2 123+;<23'1;+4.-. 3.
/'.2/'4;+&+;1.+?,,1-/'.2/'.+(/(3'3(2
-(,/.13-3/1712.1 .13'2;-3'2(2. 1(.+(/(-
G-&3+B?USSWI7TXW[X[ZVJHBI27//+(;
?1USS[J
:@<<(-"-&1/1.3(-U[WG*
U[WH
?(-3&13.1.,/+:277-(3ZG*
[email protected] ZVH@'(2&--.2277-(3. 3'
(-3&13.1.,/+:B'(-3&13.1.,/+:22.(32
9(3'3'D31,(-+.,(-. /.+;,12
-
,(32VND-/1.22(-&. 3'2,++-7+12
T-UB+31-48+;2/+(31-21(/381(-32
-.(-&,7+4/+(2. .1,2'8-.218 .13'(2
&-BI/1.8(; [email protected]./'(+
'31.<;&.72 .19'.+&-+4.-(71(-&3'
/7/+23&G$+3HI
T\VUYWWTJ
::<<(-"-&1/1.3(-UUWG*
DU?U?UU?UXX?
UZH@ 7-4.-2231-21(/4.-+
1/122.1?.%-9(3'.D1/122.1I
A
T\XSXWVXJ
988;?A::<7-'131(<
TSSVZ\UUW-.-D.(-&
::=<(-"-&1/1.3(-UUX
::><(-"-&1/1.3(-UUY
::?<(-"-&1/1.3(-UUZ
:;=<(-"-&1/1.3(-UVXG*
UZS?Y?\V?UZSH
DISCUSSION
Most regions and genes in the human autosomal genome
have been deleted or mutated in at least one individual or
animal model organism, and 10 autosomes apparently do not
have any essential genes or regions. We identified 65 genes on
12 chromosomes for which deletions or loss-of-function mutations
have not been reported.
35 genes do not have knock out or loss-of-function in vivo studies,
although the apparent function of the gene has been identified,
either based on homology or in vitro functional studies. It is not
clear whether these genes represent essential genes and warrant
further in vivo studies.
5 genes were identified for which heterozygote animal models
were severely affected or embryonic lethal (INTS7, RPL9, NOLC1,
RPS13, DLL4). Notably, 3 of them are involved in ribosomal functions,
and a fourth is involved in mRNA processing. We propose that
these genes may be essential to human development, as well,
and will likely not ever be observed as deleted or mutated
in recognized pregnancies or affected individuals.
Several cellular processes were represented by a number of genes,
including cell signaling, mRNA processing, transcription and/or
DNA repair, immune functions, cytoskeleton functions, and other
organelle processes – including mitochondria and ribosomes.
These studies have identified potential targets for further
investigation with respect to function and dosage sensitivity.
©2016 Laboratory Corporation of America ® Holdings. All rights reserved.