Table 3

Identified mutations and other potentially pathogenic variants in the 38 patients with previously unknown genotype. A) Patients with two clearly pathogenic variants in one gene; B) Patients with a single or no clear pathogenic variant in one gene. Mutations are described according to the latest nomenclature conventions described in HGVS

Patient#Principal mutations (p.)Principal mutations (c.)Sanger validation/segregationMutation, as predicted by (among SIFT, PPhen2 & Mutation T@ster)Additional potentially pathogenic variantsFrequency of additional variants in EVSdbGeographic originInbredBBS inclusion criteria
 ALO47p.[R160Q]; [R160Q]c.[479G→A]; [479G→A]SVPP, MTTurkeyYes (BBS1, BBS4)No
 P1p.? ; ?c.[1473+4A→G]; [1473+4A→G]SV + SMT (Ex14 splice site altered]TunisiaYes*Yes
 P9p.? ; ?c.[1110G→A]; [1110G→A]SV + SMT (Ex11 splice site altered]AHI1/JBTS3: p.[R830W]; [=]2.83%TunisiaYes*No
 AMK19p.? ; [M390R]c.[951+1G→A]; [1169T→G]SV + SMT (Ex10 splice site altered]; STTC21B/NPHP12: p.[R713I]; (=), BBS7: p.[D412G]; [=]NF, 0.23%NANANo
 P12p.[A14Lfs*28] ; [A14Lfs*28]c.[39del]; [39del]SV + SMTTunisiaYes*Yes
 P11p.[R146*]; [R146*]c.[436C→T]; [436C→T]SV + SMTCCDC28B: Ex2 splice site altered (F110F]; [=]2.07%TunisiaYes*Yes
 AIO57p.[E224K]; [E224K]c.[670G→A]; [670G→A]SVS, PPNPHP3: p.[R1074H]; (=), ALMS1: p.[S2102L]; [=]0.01%, 3.07%MoroccoYes (BBS1, BBS3, NPHP5, JBTS2)No
 P2p.? ; ?c.[345+5G→A]; [345+5G→A]SV + S(Ex2 splice site altered]TunisiaYes*Yes
 AGL23p.[H665Tfs*11]; [H665Tfs*11]c.[1992del]; [1992del]SV + SMTTTC21B/NPHP12: p.[R616C]; [=]0.31%IndiaYes (ALMS1, NPHP1, NPHP3, NPHP6, NPHP8]No
 P7p.[R189*]; [R189*]c.[565C→T]; [565C→T]SV + SMTNPHP4: p.[R674H]; [R674H]NFTunisiaYes*Yes
 AKX44p.[R272*]; [R272*]c.[814C→T]; [814C→T]SVMTSDCCAG8/BBS16: p.[Q505E]; [=]NFAlgeriaYes (BBS7, BBS12, NPHP8)Yes
 ALG76p.[L209P]; [L209P]c.[626T→C]; [626T→C]SV + SS, PP, MTTurkeyYes (BBS2, NPHP8)Yes
 ALG42p.[del Ex1-3]; [del Ex1-3]c.[(?_−30)_(123+?))del; [(?_−30)_(123+?)]delSV + STurkeyYes (ALMS1, BBS3, BBS4, BBS9, BBS14, NPHP2, NPHP3)Yes
 P3p.[del Ex4-5-6] ; [del Ex4-5-6]c.[(157−?)_(405+?)del]; [(157−?)_(405+?)del] (g.[24029..24285]_(33661..34498))del];g.[24029..24285]_(33661..34498))del]SV + SBBS5: p.[N184S]; [=]0.57%TunisiaYes*Yes
 P13p.[L50R]; [L50R]c.[149T→G]; [149T→G]SV + SS, PP, MTTunisiaYes*Yes
 ALG5p.[R138H]; [R138H]c.[413G→A]; [413G→A]SV + SS, PP, MTFranceNoNo
 P10p.? ; ?c.[1272+1G→A]; [1272+1G→A]SV + SMT (Ex5 splice site altered)NPHP4: p.[R959Q]; [=]NFTunisiaYes*Yes
 P14p.? ; ?c.[329+1G→A]; [329+1G→A]SV + SMT (Ex4 splice site altered]AHI1/JBTS3: p.[R830W]; [=]2.83%TunisiaYes*Yes
 P8p.[S396Lfs*6]; [S396Lfs*6]c.[1171_1181dupGCATTTATACC]; [1171–1181dupGCATTTATACC]SV + SMTTunisiaYes*Yes
 JSLp.[V707*]; [R95S]c.[2119–2120delGT]; [285A→T]SV + SMT; S, PP, MTNANANA
 BBH64p.[T483Nfs*8]; [?]c.[1448–1452delCTCAA]; [?]SMTCCDC28B: Ex2 splice site altered (F110F) ; (=]2.07%NANoNo
 AMR64p.[L414S]; [L414S]c.[1241T→C]; [1241T→C]SVS, PPCCDC28B: Ex2 splice site altered (F110F) ; (=]2.07%NANAYes
 AKR68p.[L414S]; [L414S]c.[1241T→C]; [1241T→C]SVS, PPCEP290/BBS14: p.[K1870Nfs*4]; [=]NFNAYes (BBS10, JBTS3)No
 AIA84p.[E1114Rfs*9); (E1114Rfs*9]c.[3340del]; [3340del]SVMTTurkeyYes (ALMS1, BBS14)Yes
 AKO26p.[R3629*]; [R3629*]c.[10885C→T]; [10885C→T]SV + SMTWDPCP/BBS15: p.[V329M]; (=), AHI1/JBTS3: p.[R548H]; [=]0.13%, 1.65%FranceYes (ALMS1, BBS12)Yes
 ALB64p.[S577*]; [S577*]c.[1730C→G]; [1730C→G]SV + SMTIQCB1/NPHP5: p.[E481K]; [=]0.17%PortugalYes (BBS7, BBS12, BBS14, ALMS1)No
Patient#GenePotential mutations (p.)Potential mutations (c.)Frequency in EVSdbMutation, as predicted by (among SIFT, PPhen2 & mutation T@ster)Geographic originConsanguinityBBS inclusion criteria
AHR2BBS3/ARL6p.[D179N]; [=]c.[535G→A]; [=]NFMT (Ex8 splice site altered]ReunionYes. BBS3, JBTS3No
AIY87BBS9p.[P641S]; [=]c.[1921C→T]; [=]NFS, PP, MTNAYes: BBS5, ALMS1, NPHP12, NPHP5, BBS14No
AKE98ALMS1p.[P2679L]; [P2679L]c.[8036C→T]; [8036C→T]NFS, PMelanesiaYes: BBS12, BBS9, CEP290, NPHP1, MKS1Yes
NPHP4p.[V1228G]; [=]c.[3683T→G]; [=]0.10%S, P
NPHP3p.[A519G]; [=]c.[1556C→G]; [=]NFP, MT
INVS/NPHP2p.[N1061Kfs*20]; [N1061Kfs*20]c.[3176_3177insA]; [3176_3177insA]NF
AIX45TMEM67/ NPHP11p.[Y486C]; [=]c.[1457A→G]; [=]0.01%P, MTNAYesYes
AMA28MKKS/BBS6p.[A242S]; [=]c.[724GT]; [=]0.58%S, PFranceNoYes
NPHP1p.[E569G]; [=]c.[1706A→G]; [=]NFS, P, MT
AMO77TTC21B/ NPHP12p.[R863W]; [=]c.[2587C→T]; [=]0.23%S, P, MTNANAYes
AHL86AHI1/JBTS3p.[R830W]; [=]c.[2488C→T]; [=]2.83%S, P, MTNANANo
INVS/NPHP2p.[T122P]; [=]c.[364A→C]; [=]NFS, P, MT
  • * Patients from consanguineous families, but not genotyped on affymetrix SNP arrays. In bold: previously reported mutations in other studies. Mutation prediction software equivalents: possibly/probably damaging (polyphen2), damaging (SIFT), disease causing (mutation taster). Ex, exon; S, SIFT; PP, PolyPhen2; MT, mutation T@ster.

  • (?): The exact nature of the second heterogeneous mutation could not be identified by high-throughput sequencing. An abnormal loss of coverage is observed at the very end of BBS10. The exact nature of this apparently complex mutation is still under investigation by direct sequencing, but appears to involve an alu insertion coupled with a duplication/inversion. Amino acid conservation of non-reported missense mutations is shown in supplementary figure S4. SV: Sanger validation; S: segregation validated.

  • Consanguinity was documented by clinicians, and in most cases, BBS patients from consanguineous families were genotyped on Affymetrix 250k SNP arrays. When so, BBS and other targeted genes located within homozygous regions are thus indicated in ( ).