Supplementary Table 1:

Published mutations in MKS3/TMEM67 in 19 families with Meckel-Gruber and 12families with Joubert/COACH syndrome

Disease / Family ID / Nucleotide
change / Deduced
protein change / Type of mutation for each allele / CNS / Kidney / Liver / Eye / Other / Literatur
MKS / 125 / c.383-384delAC / p.H128fsX140 / Frameshift
Frameshift / OE, DW / RCD / HDD / PD / Smith et al., 2006
MKS / 67F / c.647delA / p.E216fsX221 / Frameshift
Frameshift / OE / RCD / HDD / CP
MKS / 73 / IVS8-2A>G / Splice / Splice
Splice / OE / RCD / HDD
MKS / 40T / c.1127A>C / p.Q376P / Missense
Missense / OE / RCD / HDD / CP, EC
MKS / 29A
33A / IVS15+1G>A / Splice / Splice
Splice / OE
OE / RCD / HDD / PP
MKS / 1 / c.1336G>C
c.2439G>A / p.D446H
p.A813A, splice / Missense
Splice / MC, OE / RCD / BDP / PD / Khaddour
et al., 2007
MKS / 2 A
B / c.1046T>C
c.2557A>T / p.L349S
p.K853X / Missense
Nonsense / OM, CVA
OE / RCD / BDP
?
MKS / 3 A
B / c.1065+1delG / Splice / Splice
Splice / OE,
DW / RCD / ?
? / CP
MKSb / 4 A
B / c.622A>T
c.755T>C / p.R208X
p.M252T / Nonsense
Missense / OE
normal / RCD
RCD / ?
BDP / PD
MKS / 5 / c.651+2G>T
c.1319G>A / Splice
p.R440Q / Splice
Missense / OM / RCD / BDP / CP
MKS / 6 / c.1675-?_2241+?del / p.T559_Q747del / Deletion
Deletion / MC, OE / RCD / BDP
MKS / 7 / c.1575+1G>A / Splice / Splice
Splice / DW / RCD / BDP / Co
MKS / 8 A
B / c.1575+1G>A / Splice / Splice
Splice / OE
OE / RCD
RCD / ?
BDP
MKS / 9 / c.870-2A>G / Splice / Splice
Splice / OE / RCD / BDP
MKS / M329 A
B
C / c.1351C>T
c.622A>T / p.R451X
p.R208X / Nonsense
Nonsense / OE
OE
N/A / RCD
RCD
RCD / DPM
N/A
N/A / Consugar
et al., 2007
MKSb / M360 A
B / c.622A>T
c.755T>C / p.R208X
p.M252T / Nonsense
Missense / EH
OE / RCD
RCD / Enlarged
N/A / -
PD
MKS / M361 A
B
C
D
E / c.2897T>C
c.1319G>A / p.L966P
p.R440Q / Missense
Missense / OE
OE
NAD
DW
NAD / RCD
RCD
RCD
RCD
RCD / N/A
N/A
N/A
DPM
DPM
MKS / M376 / IVS1-2delA
c.755T>C / Splice
p.M252T / Splice
Missense / OE / RCD / Enlarged,
DPM
MKS / 68408 / c.622A>T
c.579delA / p.R208X
p.T193fsX221 / Nonsense
Frameshift / OE
OE / N/A
RCD / N/A
N/A
JBTS / 1 A
B / c.1583A>G
c.2315_2323+4
del 13insGG / p.Y513C
Splice / Missense
Splice / CVH
CVH / Microcysts,
Microcysts / HF, BDP
HF, BDP / Baala
et al., 2007
JBTS / 2 / IVS23+5G>C / p.I775_A813del / In frame del
In frame del / HT, MR, BA, CVH, MTS / - / -
JBTS / 3 / IVS6+2T>G
c.1634G>A
c.2341G>A / Splice
p.G545E
Splice / Splice
Missense
Splice / HT, AT, CVH, MTS / - / - / OMA
JBTS / 4 / c.637C>T
c.2132A>C / p.R213C
p.D711A / Missense
Missense / AT, MR, CVH / Microcysts / Liver disease
COACH / Cor09_a
Cor09_b / c.1769T>C
c.G1961-2A>C / p.F590S
Splice / Missense
Splice / MTS, HT, AT, DD, MR
MTS, HT, DD, MR / -
- / ELE, HF, HM, EV, LT,
ELE, HF, HM, EV / OMA, Ny
OMA, Ny / -
- / Brancati
et al., 2008
COACH / COR20_a
COR20_b / c.579_580delAG
c.1769T>C / p.G195IfsX13
p.F590S / Frameshift Missense / MTS, AT, DD, MR
MTS, HT, AT, DD, MR, / -
- / ELE, HF,
HF / OMA, Ny
OMA / -
-
COACH / COR32_a
COR32_b / c.1115C>A
c.2345A>G / p.T372K
p.H782R / Missense
Missense / MTS, AB, HT, DD, MR,
MTS, HT, DD / RKA
- / BDD, HM
ELE / OMA,CoOMA,Co, Ny / -
-
COACH / COR71 / c.389C>G
c.675G>A / p.P130R
p.W225X / Missense
Nonsense / MTS, HT, AT, DD, MR, / NPHP, ESRF / ELE, HF, HM / OMA, Co / HR
COACH / COR94 / c.1319G>A
c.2182A>G / p.R440Q
p.S728G / Missense
Missense / MTS, AB, HT, DD, MR / - / ELE, HF, HM / OMA, Co, Ny / HR
COACH / COR190 / c.G312+5G>A
c.2498T>C / Splice
p.I833T / Splice
Missense / MTS, OE, AB, HT, AT, DD, MR, Sz / NPHP, CRF / ELE, BDD, HM / OMA, EOC / HR
COACH / COR191_a
COR191_b / c.2460A>C
? / p.R820S
? / Missense / MTS, AB, AT, DD, MR, Sz
CVA, OE / NPHP, ESRF
CK / ELE, HF, HM
HF / POD, Ny
- / HR
PD
COACH / MTI124_a
MTI124_b / c.2498T>C
c.G2556+1G>T / p.I833T
Splice / Missense
Splice / CVA, HT, AT, DD, MR
CVA, HT, AT, DD, MR / NPHP, ESRF
NPHP, CRF / ELE, HF, HM
HF, HM, EV / Co
Ny

aNumbering is based on MKS3/TMEM67 human reference protein sequence NM_153704.5. bPatient #4 described by Khaddour et al. is the same patient as patient #M360 published by Consugar and colleages. Truncating mutations, i.e. deletions, nonsense, frameshift, , splice site mutations are highlighted in bold.AB, abnormal breathing; AT, ataxia; BA, breathing anomalies; BDD, bile duct dilatation; BDP, bile duct proliferation of liver; Co, coloboma; CK, cystic kidneys; CP, cleft palate; CVA, cerebellar vermis aplasia; CVH, cerebellar vermis hypoplasia; CRF, chronic renal failure; del, deletion; DD, developmental delay; DPM, ductal plate malformation; DW, Dandy Walker malformation; EC, epididymal cysts; ELE, elevated liver enzymes; EOC, enlarged optic cup; ESRF, end-stage renal failure; EV, esophageal varices; HDD, hepatic developmental defects; HF, hepatic fibrosis; HM, hepatomagaly; HR, hyperreflexia; HT, hypotonia; LT, liver transplant; MC, microcephaly; MR, mental retardation;MTS, molar tooth sign, N/A, no information available; NAD, nothing abnormal detected; NPHP, nephronophthisis;Ny, Nystagmus; OE, occipital encephalocele; OM, occipital meningocele;OMA, oculomotor apraxia; PD, polydactyly; POD, pale optic disc; RCD, renal cystic dysplasia; RKA, right kidney agenesis; Sz, seizures

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