Background
Methods
Patients
Molecular analysis
STR genotyping
Sanger sequencing of SLC26A4 coding region
MLPA analysis
Massive parallel sequencing and bioinformatic analysis
Results
Cohort | Patient | Nucleotide | Protein | Location | Deafness variation database | SIFT (score), PolyPhen2 (score), MutationTaster (score), Splice Prediction Tools | 1000 g | ESP6500 | Conclusion (According to ACMG criteria) | Genotype | Protein locationb |
---|---|---|---|---|---|---|---|---|---|---|---|
Families with autosomal recessive inheritance |
6
|
c.1003 T > G
a
|
p.F335V
a
|
exon 9
|
–
|
Damaging (0.003), Probably damaging (0.99), Disease causing (0.99)
|
–
|
–
|
likely pathogenic
|
Compound heterozygosis
|
External loop
|
c.1553G > A
a
|
p.W518X
a
|
exon 14
|
–
|
-, −, Disease causing (1)
|
–
|
–
|
pathogenic
|
C-terminal
| |||
7 | c.15C > A | p.G5G | exon 2 | benign | – | 0.006 | 0.005 | benign | – | – | |
IVS10 + 35G > T | – | intron 10 | benign | – | 0.003 | 0.003 | benign | – | – | ||
24
|
c.84C > A
|
p.S28R
|
exon 2
|
Likely Pathogenic
|
Damaging (0.003), Possibly damaging (0.92), Polymorphism (0.79)
|
0
|
0
|
likely pathogenic
|
Compound heterozygosis
|
N-terminal
| |
IVS19 + 2 T > C
a
|
SS
a
|
intron 19
|
–
|
-, −, Disease causing (1),
splice donor site abolished
|
–
|
–
|
pathogenic
|
C-terminal
| |||
44 | c.218A > G | p.E73G | exon 3 | – | Tolerated (0.313), Benign (0.00), Disease causing (0.77) | – | – | benign | – | – | |
IVS15-18 T > A | – | intron 15 | benign | – | 0.013 | 0.02 | benign | – | – | ||
51 | IVS15 + 76G > C | – | intron 15 | benign | – | 0.039 | 0 | benign | – | – | |
c.1826 T > G | p.V609G | exon 17 | benign | Tolerated (0.54), Benign (0.00), Polymorphism (0.19) | 0.04 | 0.049 | benign | – | – | ||
c.2130C > T | p.D710D | exon 19 | benign | – | 0.019 | 0.023 | benign | – | – | ||
c.2218G > A | p.G740S | exon 19 | benign | Tolerated (0,091), Benign (0.00), Polymorphism (0.99) | 0.015 | 0.017 | benign | – | – | ||
Cases of deafness with suspected PS and/or presenting EVA or other cochleovestibular malformation |
71
|
c.1246A > C
|
p.T416P
|
exon 10
|
Pathogenic
|
Damaging (0.00), Probably damaging (1.00), Disease causing (0.99)
|
0
|
0
|
likely pathogenic
|
Heterozygosis (monoallelic)
| TM10/Cytosolic Interface |
76 | c.898A > C | p.I300L | exon 7 | benign | Damaging (0.02), Probably damaging (0.97), Disease causing (0.99) | 0.005 | 0.004 | benign | – | – | |
78 | IVS8-143 T > C | intron 8 | – | – | – | – | benign | – | – | ||
83
|
IVS7 + 2 T > C
|
SS
|
intron 7
|
Pathogenic
|
-, −, Disease causing (1)
|
0
|
0
|
pathogenic
|
Heterozygosis (monoallelic)
| TM7 | |
85 | IVS15-18 T > A | – | intron 18 | benign | – | 0.013 | 0.022 | benign | – | – |
Patient | Gene | Nucleotide | Protein | dbSNP | Deafness Variation Database | SIFT (score), PolyPhen2 (score), MutationTaster (score), Splice Prediction Tools | 1000g | ESP6500 | Abraom |
---|---|---|---|---|---|---|---|---|---|
71 |
SLC26A4
|
c.1246A>C
|
T416P
|
rs28939086
|
Pathogenic
|
Damaging (0), Probably Damaging (0.995), Disease causing (0.971541)
|
0.0000
|
0.0000
|
0.0000
|
GJB2
| c.457G>A | V153I | rs111033186 | benign | Tolerated (1), Benign (0.007), Disease causing (0.8156) | 0.0013 | 0.00223 | 0.0032 | |
TMIE
| c.218C>T | T73M | rs770957465 | unknown significance | Tolerated (0.156), Probably Damaging (1), Disease causing (0.999) | 0.000 | 0.000 | 0.000 | |
USH1C
|
c.1823C>G
|
P608R
|
rs41282932
|
Pathogenic
|
Damaging (0.002), Probably Damaging (0.984), Disease causing ( 0.9815)
|
0.000
|
0.001
|
0.000
| |
MIR96
| 129414574A>G | rs41274239 | benign | - | 0.0010 | 0.0033 | 0.0032 | ||
PCDH15
| c.4109_4110insGCCGCC | p.P1370delinsPPP | - | not described | -, -. Polymorphism (0.999) | 0.0018 | 0.000 | 0.0016 | |
PCDH15
| c.5134_5136del | p.1712_1712del | rs397517462 | not described | -, -. Polymorphism (0.999) | 0.000 | 0.031 | 0.0032 | |
83 |
SLC26A4
|
c.918+2T>C
|
-
|
-
|
Pathogenic
|
-, -, Disease causing (1),
splice donor site abolished
|
0.000
|
0.000
|
0.0008
|
MYO7A
|
c.2463G>C
|
Q821H
|
-
|
not described
|
Damaging (0), Probably Damaging (1), Disease causing (0.9999)
|
0.000
|
0.000
|
0.000
| |
GJB6
|
c.460T>A
|
F154I
|
-
|
not described
|
Damaging (0.022), Damaging (0.986), Disease causing (0.9987)
|
0.000
|
0.000
|
0.000
| |
P2RX2
| c.A275G | p.Q92R | rs142844880 | unknown significance | Tolerable (0.116), Benign (0.098), Disease causing (1) | 0.0004 | 0.0004 | 0.000 | |
POLD1
| c.C211T | p.P71S | not described | Tolerable (0.879), Benign (0), non-disease causing (1) | 0.000 | 0.000 | 0.000 | ||
TSPEAR
| c.1185G>T | E395D | rs143303485 | not described | Tolerated (0.420), Benign (0.02), Polymorphism | 0.0002 | 0.0002 | 0.000 |