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Table 4 Diagnosis achieved using the NGS-LSD tool

From: Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders

PC

AO

GDD

IS

GENE

OMIM

REF SEC

NT CHANGE

AA CH

MT

SS

PP

CS

ZIG

MD

BA

DIAGNOS

P1

2Y

10Y

Mod

CLN5

608102

NM_006493

c.335G > C/c.835G > A

p.R112P/p.D279N

099/0.99

0/0.16

1/1

+

HO

+

NA

Finnish variant late infantile CLN

P2

4Y

4Y

Mod

CLN6

606725

NM_017882

c.794_796del

p.S265del

-

-

-

 

HO

+

NA

Early juvenile late infantile CLN

P3

3Y

12Y

High

CLN3

607042

NM_000086

c.461-280_677 + 382del966

p.[Gly154Alafs*29, Val155_Gly264del]

-

-

-

 

HO

+

NA

Juvenile CLN

P4

2Y

21Y

Mod

MFSD8

611124

NM_152778

c.881C > A

p. T294K

0.99

0

0.99

+

HO

+

NA

Turkish variant late infantile CLN

P5

4Y

12Y

High

CLN3

607042

NM_000086

c.371_372insT

p.Y124fs

-

-

-

 

HO

-

NA

Juvenile CLN

P6

3Y

4.5Y

High

ARSA

607574

NM_000487

c.465 + 1G > A

----------

-

-

-

+

HO

+

+

Metachromatic leukodystrophy

P7

1Y

8Y

Low

GLB1

611458

NM_000404

c.922 T > C

p.F308L

0.99

0

1

+

HO

-

+

GM1 gangliosidosis

P8

3Y

1Y

High

HEXA

606869

NM_000520

c.533G > A

p.R178H

0.99

0

1

+

HO

+

+

GM2 gangliosidosis, B1variant

P9

4Y

10Y

Low

HEXA

606869

NM_000520

c.1496G > A

p.R499H

0.99

0

1

 

HT

+

+

GM2 gangliosidosis, juvenil (TS)

    

HEXA

 

NM_000520

c.1003A > T

p.I335F

0.99

0

0.97

 

HT

+

  

P10

3Y

7Y

High

GLB1

611458

NM_000404

c.602G > A

p.R201H

0.99

0.02

1

 

HT

+

+

GM1 gangliosidosis

    

GLB1

 

NM_000404

c.1188_1188dupG

p.P397fs

-

-

-

 

HT

-

  

P11

5Y

18Y

High

HEXA

606869

NM_000520

c.155C > A

p.S52X

-

-

-

+

HT

+

+

GM2 gangliosidosis juvenile (TS)

    

HEXA

 

NM_000520

c.1305C > T

p.Y435Y

-

-

-

 

HT

-

  

P12

13Y

6Y

Low

NPC2

 

NM_006432

c.441 + 1G > A

-----------

-

-

-

 

HT

-

-

Niemann-Pick disease, type C2?

P13

18 M

3Y

High

GNPTAB

607840

NM_024312

c.2354 T > G

p.L785W

0.71

0.09

0.022

+

HT

-

+

Mucolipidosis II/III

    

GNPTAB

 

NM_024312

c.1774G > A

p.A592T

0.98

0.01

0.955

 

HT

-

  

P14

12 M

4Y

High

HEXA

606869

NM_000520

c.718_719insT

p.K240fs

    

HT

-

+

GM2 gangliosidosis (TS)

    

HEXA

 

NM_000520

c.1003A > T

p.I335F

0.99

0.00

0.467

 

HT

+

  

P15

0 M

1Y

High

GLB1

611458

NM_000404

c.671_672delAT

p.H224Qfs

   

+

HO

-

+*

GM1 gangliosidosis

P16

9 M

1Y

High

ARSB

611542

NM_000046

c.382_384delCTC

p.L128del

    

HO

-

+*

Mucopolysaccharidosis VI

P17

0 M

3Y

High

GNPTAB

607840

NM_024312

c.3739_3742delCTTT

p.E1248fs

   

+

HO

-

+

Mucolipidosis II/III

P18

2 M

6Y

High

IDS

300823

NM_000202

c.425C > T

p.S142F

0.98

0.00

0.998

+

HE

+

+*

Hunter Syndrome

P19

3Y

5Y

High

IDUA

252800

NM_000203

c.1205G > A

p.W402X

   

+

HT

+

+*

Hurler Syndrome

    

IDUA

 

NM_000203

c.1874A > G

p.Y625C

0.98

0.00

0.99

 

HT

-

  

P20

10 M

2Y

High

GLB1

611458

NM_000404

c.947A > G

p.Y316C

0.999

0

0.79

 

HT

+

+*

GM1 gangliosidosis

    

GLB1

 

NM_000404

c.458-401_552 + 1033del1529

-----------

    

HT

+

  

P21

20 M

4Y

High

HEXA

606869

NM_000520

c.459 + 5G > A

-----------

    

HT

+

+*

GM2 gangliosidosis (TS)

    

HEXA

 

NM_000520

c.533G > A

p.R178H

0.99

0

1

 

HT

+

  

P22

2Y

4Y

High

CLN8

607837

NM_018941

c.509C > G

p.T170R

0.999

0.00

0.999

+

HO

+

NA

Ceroid lipofuscinosis, neuronal, 8

P23

3Y

9Y

High

CTSD

116840

NM_001909

c.470C > T

p.S157L

0.98

0.03

0.005

+

HT

-

NA

Ceroid lipofuscinosis, neuronal, 10

    

CTSD

 

NM_001909

c.353-12G > A

-----------

-

-

-

 

HT

-

pendε

 

P24

3Y

23Y

High

HGSNAT

610453

NM_152419

c.1250 + 1G > A

-----------

-

-

-

 

HT

+

+*

Sanfilippo C

    

HGSNAT

 

NM_152419

c.1270G > A

p. G424S

0.999

0.59

1

 

HT

+

  

P25

1Y

6Y

High

GM2A

613109

NM_000405

c.333delC

p. C112Vfs

-

-

-

 

HO

-

+#

GM2 gangliosidosis, AB variant

P26

4Y

>20Y

High

CLN8

607837

NM_018941

c.792C > G

p. N264K

0.97

0

0.99

+

HO

-

NA

Ceroid lipofuscinosis, neuronal, 8

  1. Notes and abbreviations: Samples from Patients P1-P12 were processed using SOLiD4 (Life Technologies), but those from P13-P26 using HiSeq2000 (Illumina); PC: Patient Code; AO: Age of Onset (Y: years; M: months); GDD: Genetic Diagnosis Delay (Y: years; M: months: DEC: deceased); IS: index of suspicion of LSD (Mod: moderate); REF SEC: reference sequence for which mutations are annotated; Nt and Aa Change: nucleotide and amino acid change (population frequency ≤0.01 according to 1000G2012 database); MT: Mutation Taster, SS: Sift Score and PP: Polyphen 2 score (in silico values to assess pathogenicity of missense variants); CS: Cosegregation; ZIG: zigosity; HO: homozygote; HT: heterozygote; HE: hemizygous; MD: Mutation description in Human Gene Mutation Database (+: previously associated with pathology; −: not previously associated); BA: Biochemical assay (+: positive; NA: test not available; −: negative); CLN: Neuronal Ceroid Lipofuscinosis; TS: Tay-Sachs; *Levels detected before NGS-LSD assay; εmRNA splicing analysis; #histopathology congruent with GM2 diagnosis.