Fig. 1Pedigree of this family. Brachydatylies are found in every generations in both genders indicating autosomal dominant trait of inheritance. Open, unaffected; closed, affected. aProband.
Fig. 2Clinical phenotypes of the proband and his mother: (A) right hand of the proband; (B) left hand of the mother; (C) right foot of the proband; (D) left foot of the mother, note the shortening of the 4th and 5th metacarpals and 4th and 5th metatarsals; (E) radiological feature of the mother's left feet showing shortening of 4th and 5th metatarsals. In addition, premature fusion of the epiphyses is noted in the shortened bones.
Fig. 3Filters used in analysis of the exome data and numbers of candidate variants. The autosomal dominant variants identified by whole exome sequencing were represented by the Venn diagram. After filtering, a total of 8,908 variants were identified as being shared by the two affected subjects.
Fig. 4Schematic structure of PTHLH (parathyroid hormone like hormone) gene. Mutations reported in the literature that were associated with brachydactyly type E are indicated in black in addition to the c.169C>T mutation identified in this study in red.
Table 1Steps of Filtering
Filter |
Recessive |
Dominant |
Compound heterozygous |
Raw |
2,435 |
6,663 |
4,051 |
Filter 1 |
470 |
1,519 |
1,446 |
Filter 2 |
132 |
625 |
426 |
Filter 3 |
83 |
451 |
252 |
Filter 4 |
10 |
149 |
113 |
Filter 5 |
4 |
147 |
108 |
Table 2Twenty Three Variants Remained after Advanced Steps for the Identification of the Disease-Causing Mutation
Chromosome |
Gene |
HGVS_Ca
|
HGVS_Pb
|
Home/Hetero |
Primate |
Placental |
Vertebrate |
chr3 |
PCYT1A
|
c.1010C>T |
p.Pro337Leu |
Hetero |
0.655000 |
2.941000 |
9.434000 |
chr1 |
PRUNE
|
c.1058C>G |
p.Pro353Arg |
Hetero |
0.655000 |
2.941000 |
6.164000 |
chr9 |
NFX1
|
c.3095G>A |
p.Arg1032Gln |
Hetero |
0.655000 |
2.884000 |
3.982000 |
chr2 |
NEB
|
c.21961G>A |
p.Asp7321Asn |
Hetero |
0.655000 |
2.838000 |
7.345000 |
chr6 |
LGSN
|
c.1205G>C |
p.Gly402Ala |
Hetero |
0.655000 |
2.832000 |
4.350000 |
chr11 |
PRDM10
|
c.2798C>T |
p.Ala933Val |
Hetero |
0.655000 |
2.828000 |
5.470000 |
chr3 |
FNDC3B
|
c.1354G>T |
p.Ala452Ser |
Hetero |
0.655000 |
2.825000 |
9.081000 |
chr3 |
MYLK
|
c.1327C>T |
p.Pro443Ser |
Hetero |
0.655000 |
2.822000 |
5.120000 |
chr5 |
PCDHAC2
|
c.1345C>T |
p.Leu449Phe |
Hetero |
0.655000 |
2.818000 |
2.507000 |
chr8 |
PCMTD1
|
c.743G>A |
p.Arg248His |
Hetero |
0.655000 |
2.722000 |
7.046000 |
chr17 |
SMG8
|
c.1585G>T |
p.Ala529Ser |
Hetero |
0.655000 |
2.705000 |
8.006000 |
chr3 |
STAC
|
c.472C>T |
p.Arg158Trp |
Hetero |
0.655000 |
2.683000 |
5.082000 |
chr8 |
PABPC1
|
c.1205C>T |
p.Pro402Leu |
Hetero |
0.655 |
2.678 |
9.831 |
chr6 |
PPIL1
|
c.107G>C |
p.Cys36Ser |
Hetero |
0.655000 |
2.673000 |
7.430000 |
chr3 |
KIAA0226
|
c.2126C>T |
p.Thr709Met |
Hetero |
0.655 |
2.629 |
6.691 |
chr3 |
MST1
|
c.1951C>T |
p.Arg651*
|
Hetero |
0.655 |
2.621 |
3.489 |
chr2 |
TTN
|
c.14984C>G |
p.Pro4995Arg |
Hetero |
0.650000 |
2.779000 |
5.707000 |
chr20 |
PLCB4
|
c.2822C>A |
p.Ser941Tyr |
Hetero |
0.650000 |
2.761000 |
5.182000 |
chr2 |
ATRAID
|
c.394C>T |
p.Leu132Phe |
Hetero |
0.650000 |
2.665000 |
3.904000 |
chr12 |
PTHLH
|
c.169C>T |
p.Arg57*
|
Hetero |
0.650000 |
2.660000 |
2.680000 |
chr4 |
COQ2
|
c.1016C>T |
p.Ala339Val |
Hetero |
0.650000 |
2.639000 |
6.513000 |
chr4 |
HHIP
|
c.616G>C |
p.Glu206Gln |
Hetero |
0.643000 |
2.817000 |
9.169000 |
chr6 |
MTHFD1L
|
c.1691G>A |
p.Arg564His |
Hetero |
0.609000 |
2.780000 |
9.512000 |