Table 1

Genetic and clinical data of probands with a pathogenic point mutation in genes associated with obesity

GeneMutation (zygosity)IDCarriers, nPatho-genicityMAF in gnomADSexAge (years)BMI SDS for age (children) BMI (adults)PhenotypeLeptin (ng/mL)Insulin (μIU/mL)Cortisol (μg/dL)
LEPc.-29+1G>C/p.? (hmz)#132, #155, #237, #255, #297, #3426P0M: 2
F: 4
3.9 ± 0.99.1 ± 0.9Excessive adiposity: #297, #342; hepatomegaly: #342; splenomegaly: #237; sleep apnea: #237, #342; delayed milestonesND9.2 ± 2.513.0 ± 1.0
LEPc.398delG/p.G133Vfs*15 (hmz)#130, #134, #138, #143, #153, #157, #162, #172, #194, #195, #199, #206, #228, #241, #261, #264, #262, #276, #278, #279, #281, #284, #289, #292, #295, #296, #305, #311, #322, #323, #324, #325, #326, #330, #344, #352, #341, #127, #15439P0.00003 (7/245,914)M: 25
F: 14
2.0 ± 0.421 (#127)§
25 (#154)§
8.4 ± 0.542 (#127)
50 (#154)
Excessive adiposity: #206; undescended testes: #228; hepatomegaly: #264, #295; dyspnea: #264; hypersomnia: #305, #341; recurrent RTI: #228, #261, #262, #279, #281, #289, #295, #296, #330, #352; delayed milestonesND21.8 ± 3.112 (#127)
36 (#154)
17.6 ± 1.331 (#127)
9 (#154)
LEPc.104_106del/p.I35del (hmz)#345, #3362P0.00001 (2/246,258)M: 1
F: 1
10 (#345)
1.3 (#336)
3.7 (#345)
13.2 (#336)
Excessive adiposity: #345; polyuriaND26 (#345)
17 (#336)
12 (#345)
15 (#336)
LEPc.309C>A/p.N103K (hmz)#300, #2932P0.00175 (430/24,625)F1.5 (#300)
0.7 (#293)
7.2 (#300)
9.7 (#293)
Excessive adiposity, delayed milestones32 (#300)Π
83 (#293)Π
17 (#300)
9 (#293)
14 (#300)
16 (#293)
LEPc.314G>A/p.R105Q (hmz)#3091LP0F1.86.7Excessive adiposity, recurrent RTIND59
LEPc.298G>A/p.D100N (hmz)#2491P0.00000 (1/246,244)M2.014.0Excessive adiposity12Π1112
LEPc.417del/p.Y140Tfs*8 (hmz)#2201P0F0.88.0Excessive adiposityND3612
LEPRc.2396–2A>G/p.? (hmz)#183, #3542P0M: 1
F: 1
18 (#183)§
0.7 (#354)
64 (#183)
1.3 (#354)
Excessive adiposity: #183; delayed milestones: #354; recurrent RTI277 (#183)
136 (#354)
25 (#183)
19 (#354)
10 (#183)
15 (#354)
LEPRc.2396–1G>T/p.? (hmz)#248, #3212P0.00040 (1/250,546)M: 1
F: 1
0.4 (#248)
0.6 (#321)
8.4 (#248)
7.5 (#321)
Excessive adiposity38 (#248)
26 #(321)
13 (#248)
18 (#321)
15 (#248)
14 (#321)
LEPRc.704–1G>A/p.? (hmz)#331, #1732P0F0.5 (#331)
2.8 (#173)
7.7 (#331)
11.4 (#173)
Excessive adiposity31 (#331)
61 (#173)
23 (#331)
36 (#173)
15 (#331)
14 (#173)
LEPRc.40G>A/p.E14K (hmz)#141P0M2.310.6Excessive adiposity5667
LEPRc.2114G>A/p.W705* (hmz)#1501P0M0.86.7Excessive adiposity30125
LEPRc.2899_2900insAT/p.A967Dfs*7 (hmz)#1701P0F0.96.4Excessive adiposity10816
LEPRc.1738del/p.E580Kfs*37(hmz)#1861P0M1.69.2Excessive adiposity191316
LEPRc.2T>C/p.? (hmz)#OB-11P0M18.5§38.6Excessive adiposity541211
LEPRc.2627C>T/p.P876L (hmz)#2831LP0.00071 (2/282,696)M0.712.2Excessive adiposity, recurrent RTI31123
LEPRc.2153A>G/p.N718S (hmz)#1421LP†0.00040 (1/251,374)F0.77.0Excessive adiposity45198
LEPRc.2213–3C>G/p.? (hmz)#3281LP†0F3.07.8Excessive adiposity, anemia, delayed milestones, aggressive behavior281717
LEPRc.3268_3269del/p.S1090Wfs*6 (hmz)#3121P0M146.6Excessive adiposity, diabetes, delayed milestones311518
MC4Rc.493C>T/p.R165W (hmz)#269, #273, #286, #3104P0.00002 (6/246,054)M: 1
F: 3
5.1 ± 1.76.7 ± 0.5Excessive adiposity22 ± 967 ± 2216 ± 6
MC4Rc.48G>A/p.W16* (hmz)#2021P0M5.313.2Excessive adiposity55164
MC4Rc.47G>A/p.W16* (hmz)#260, #3372P0M4 (#260)
2 (#337)
7.4 (#260)
9.6 (#337)
Excessive adiposity9 (#260)
11 (#337)
7 (#260)
26 (#337)
8 (#260)
13 (#337)
MC4Rc.482T>C/p.M161T (hmz)#2321LP0.000004 (1/246,124)M6.911.0Excessive adiposity, hepatomegaly, hepatosteatosis, aggressive behavior271314
MC4Rc.633_636del/p.Y212Sfs*5 (hmz)#2331P0.000004 (1/246,020)M5.78.9Excessive adiposity, bowlegs108.69
MC4Rc.601_612del/p.F201_M204del (hmz)#2391LP0F7.24.8Excessive adiposity, recurrent tonsillitis141311
MC4Rc.63_64del/p.Y21* (hmz)#2571P0.00001 (3/245,824)F4.68.0Excessive adiposity417410
MC4Rc.206T>C/p.I69T (hmz)#3081P0.000004 (1/246,114)F2.56.4Excessive adiposity104012
ADCY3c.2173–10_2185del/p.? (hmz)#3061P0F1.26.7Excessive adiposity14911
ADCY3c.3315del/p.(I1106Sfs*3)‡ (hmz)#1071P0F153.5Excessive adiposity, anosmia, amenorrhea, moderate intellectual disability304818
ADCY3c.2578–1G>A/p.?‡ (hmz)#1581P0M66.5Excessive adiposity221111
ADCY3c.191A>T/p.N64I‡ (hmz)#1741LP†0.00026 (66/250,536)M66.5Excessive adiposity, anosmia, moderate intellectual disability11187.5
BBS1c.1570_1572del/p.N524del (htz); c.48–2A>C/p.? (htz)#2521LP0 and 0.00001 (3/246,272)M1.46Excessive adiposity, polydactyl91615
BBS1c.432+1G>A/p.? (hmz)#1261P0.00001 (1/119,828)F3.26.5Excessive adiposity, polydactyl111813
BBS1c.1339G>A/p.A447T (hmz)#1841LP0.00004 (10/250,660)F44Excessive adiposity, polydactyl102218
BBS2c.406dup/p.A136Cfs*15 (hmz)#931P0M9.24.5Excessive adiposityNA47.5NA
BBS2c.116A>G/p.K39R (hmz)#2941P0.00001 (2/243,800)M11.05.0Excessive adiposity, aggressive behavior, polydactyl615710
BBS2c.1759_1762del/p.P587Sfs*10 (hmz)#3181P0M9.06.2Excessive adiposity, intellectual disability, polydactyl271910
BBS5c.668_671del/p.E223Afs*14 (hmz)#3161P0F10.35.6Excessive adiposity, bowlegs, delayed milestones, poor vision, recurrent tonsillitis148611
BBS5c.2T>A/p.? (hmz)#1981P0.000012 (3/249,784)M0.94.5Excessive adiposity, polydactyl, recurrent RTI16111
BBS5c.206T>G/p.V69G (hmz)#3351LP†0M144.1Excessive adiposity, poor vision, intellectual disability, polydactyl112111
BBS9c.662A>G/p.E221G (htz), c.635T>C/p.F212S (htz)#1281LP0F2.63.3Excessive adiposity, polydactyl, recurrent RTI14259
BBS9c.400del/p.T134Qfs*5 (hmz)#1311P0M1.59.4Excessive adiposity, polydactyl1517NA
BBS10c.271dup/p.C91Lfs*5 (hmz)#114, #732P0M1.1 (#114)
8.8 (#73)
4.9 (#114)
4.2 (#73)
Excessive adiposity, polydactyl6 (#114)
42 (#73)
3 (#114)
4 (#73)
NA
BBS10c.257T>C/p.F86S(hmz)#2141LP0M0.64.3Excessive adiposity71014
MKKSc.775del/p.T259Lfs*21(hmz)#275, #258, #3393P0.00004 (11/245,790)F1.3 (#258)
13 (#339)
10.8 (#258)
2.6 (#339)
Delayed milestones; polydactyl: #258; sleep apnea: #339; poor vision in dark25 ± 520 ± 512 ± 1
ALMS1c.4937C>A/p.S1646* (hmz)#1391P0.000004 (1/245,290)M2.56.2Excessive adiposity104812
ALMS1c.8008C>T/p.R2670* (hmz)#1401P0M1.95.8Excessive adiposity83917
ALMS1c.7436C>G/p.S2479* (hmz)#2211P0.00082 (2/245,262)M1.15.7Anemia, poor vision73614
ALMS1c.10975C>T/p.R3659* (hmz)#3381P0.000004 (1/245,694)M2.08.6Delayed milestones, poor vision12591
  • Data are mean ± SEM. hmz, homozygous; htz, heterozygous; LP, likely pathogenic; MAF, minor allele frequency; NA, not available; ND, not detectable (or <0.5 ng/mL); P, pathogenic; RTI, respiratory tract infection.

  • §Young adults (≥18 years of age).

  • ΠImmunoreactive but bioinactive leptin protein.

  • †Upgraded from VUS to LP on the basis of strong phenotypic relevancy with regard to the genetic mutation.

  • ‡Previously published by us (9).