Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan
Article Figures & Tables
Figures
- Figure 1
Genetic etiologies of obesity in a cohort of 225 patients from Pakistani consanguineous families.
Tables
- Table 1
Genetic and clinical data of probands with a pathogenic point mutation in genes associated with obesity
Gene Mutation (zygosity) ID Carriers, n Patho-genicity MAF in gnomAD Sex Age (years) BMI SDS for age (children) BMI (adults) Phenotype Leptin (ng/mL) Insulin (μIU/mL) Cortisol (μg/dL) LEP c.-29+1G>C/p.? (hmz) #132, #155, #237, #255, #297, #342 6 P 0 M: 2
F: 43.9 ± 0.9 9.1 ± 0.9 Excessive adiposity: #297, #342; hepatomegaly: #342; splenomegaly: #237; sleep apnea: #237, #342; delayed milestones ND 9.2 ± 2.5 13.0 ± 1.0 LEP c.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, #154 39 P 0.00003 (7/245,914) M: 25
F: 142.0 ± 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 milestones ND 21.8 ± 3.112 (#127)
36 (#154)17.6 ± 1.331 (#127)
9 (#154)LEP c.104_106del/p.I35del (hmz) #345, #336 2 P 0.00001 (2/246,258) M: 1
F: 110 (#345)
1.3 (#336)3.7 (#345)
13.2 (#336)Excessive adiposity: #345; polyuria ND 26 (#345)
17 (#336)12 (#345)
15 (#336)LEP c.309C>A/p.N103K (hmz) #300, #293 2 P 0.00175 (430/24,625) F 1.5 (#300)
0.7 (#293)7.2 (#300)
9.7 (#293)Excessive adiposity, delayed milestones 32 (#300)Π
83 (#293)Π17 (#300)
9 (#293)14 (#300)
16 (#293)LEP c.314G>A/p.R105Q (hmz) #309 1 LP 0 F 1.8 6.7 Excessive adiposity, recurrent RTI ND 5 9 LEP c.298G>A/p.D100N (hmz) #249 1 P 0.00000 (1/246,244) M 2.0 14.0 Excessive adiposity 12Π 11 12 LEP c.417del/p.Y140Tfs*8 (hmz) #220 1 P 0 F 0.8 8.0 Excessive adiposity ND 36 12 LEPR c.2396–2A>G/p.? (hmz) #183, #354 2 P 0 M: 1
F: 118 (#183)§
0.7 (#354)64 (#183)
1.3 (#354)Excessive adiposity: #183; delayed milestones: #354; recurrent RTI 277 (#183)
136 (#354)25 (#183)
19 (#354)10 (#183)
15 (#354)LEPR c.2396–1G>T/p.? (hmz) #248, #321 2 P 0.00040 (1/250,546) M: 1
F: 10.4 (#248)
0.6 (#321)8.4 (#248)
7.5 (#321)Excessive adiposity 38 (#248)
26 #(321)13 (#248)
18 (#321)15 (#248)
14 (#321)LEPR c.704–1G>A/p.? (hmz) #331, #173 2 P 0 F 0.5 (#331)
2.8 (#173)7.7 (#331)
11.4 (#173)Excessive adiposity 31 (#331)
61 (#173)23 (#331)
36 (#173)15 (#331)
14 (#173)LEPR c.40G>A/p.E14K (hmz) #14 1 P 0 M 2.3 10.6 Excessive adiposity 56 6 7 LEPR c.2114G>A/p.W705* (hmz) #150 1 P 0 M 0.8 6.7 Excessive adiposity 30 12 5 LEPR c.2899_2900insAT/p.A967Dfs*7 (hmz) #170 1 P 0 F 0.9 6.4 Excessive adiposity 10 8 16 LEPR c.1738del/p.E580Kfs*37(hmz) #186 1 P 0 M 1.6 9.2 Excessive adiposity 19 13 16 LEPR c.2T>C/p.? (hmz) #OB-1 1 P 0 M 18.5§ 38.6 Excessive adiposity 54 12 11 LEPR c.2627C>T/p.P876L (hmz) #283 1 LP 0.00071 (2/282,696) M 0.7 12.2 Excessive adiposity, recurrent RTI 31 1 23 LEPR c.2153A>G/p.N718S (hmz) #142 1 LP† 0.00040 (1/251,374) F 0.7 7.0 Excessive adiposity 45 19 8 LEPR c.2213–3C>G/p.? (hmz) #328 1 LP† 0 F 3.0 7.8 Excessive adiposity, anemia, delayed milestones, aggressive behavior 28 17 17 LEPR c.3268_3269del/p.S1090Wfs*6 (hmz) #312 1 P 0 M 14 6.6 Excessive adiposity, diabetes, delayed milestones 31 15 18 MC4R c.493C>T/p.R165W (hmz) #269, #273, #286, #310 4 P 0.00002 (6/246,054) M: 1
F: 35.1 ± 1.7 6.7 ± 0.5 Excessive adiposity 22 ± 9 67 ± 22 16 ± 6 MC4R c.48G>A/p.W16* (hmz) #202 1 P 0 M 5.3 13.2 Excessive adiposity 55 16 4 MC4R c.47G>A/p.W16* (hmz) #260, #337 2 P 0 M 4 (#260)
2 (#337)7.4 (#260)
9.6 (#337)Excessive adiposity 9 (#260)
11 (#337)7 (#260)
26 (#337)8 (#260)
13 (#337)MC4R c.482T>C/p.M161T (hmz) #232 1 LP 0.000004 (1/246,124) M 6.9 11.0 Excessive adiposity, hepatomegaly, hepatosteatosis, aggressive behavior 27 13 14 MC4R c.633_636del/p.Y212Sfs*5 (hmz) #233 1 P 0.000004 (1/246,020) M 5.7 8.9 Excessive adiposity, bowlegs 10 8.6 9 MC4R c.601_612del/p.F201_M204del (hmz) #239 1 LP 0 F 7.2 4.8 Excessive adiposity, recurrent tonsillitis 14 13 11 MC4R c.63_64del/p.Y21* (hmz) #257 1 P 0.00001 (3/245,824) F 4.6 8.0 Excessive adiposity 41 74 10 MC4R c.206T>C/p.I69T (hmz) #308 1 P 0.000004 (1/246,114) F 2.5 6.4 Excessive adiposity 10 40 12 ADCY3 c.2173–10_2185del/p.? (hmz) #306 1 P 0 F 1.2 6.7 Excessive adiposity 14 9 11 ADCY3 c.3315del/p.(I1106Sfs*3)‡ (hmz) #107 1 P 0 F 15 3.5 Excessive adiposity, anosmia, amenorrhea, moderate intellectual disability 30 48 18 ADCY3 c.2578–1G>A/p.?‡ (hmz) #158 1 P 0 M 6 6.5 Excessive adiposity 22 11 11 ADCY3 c.191A>T/p.N64I‡ (hmz) #174 1 LP† 0.00026 (66/250,536) M 6 6.5 Excessive adiposity, anosmia, moderate intellectual disability 11 18 7.5 BBS1 c.1570_1572del/p.N524del (htz); c.48–2A>C/p.? (htz) #252 1 LP 0 and 0.00001 (3/246,272) M 1.4 6 Excessive adiposity, polydactyl 9 16 15 BBS1 c.432+1G>A/p.? (hmz) #126 1 P 0.00001 (1/119,828) F 3.2 6.5 Excessive adiposity, polydactyl 11 18 13 BBS1 c.1339G>A/p.A447T (hmz) #184 1 LP 0.00004 (10/250,660) F 4 4 Excessive adiposity, polydactyl 10 22 18 BBS2 c.406dup/p.A136Cfs*15 (hmz) #93 1 P 0 M 9.2 4.5 Excessive adiposity NA 47.5 NA BBS2 c.116A>G/p.K39R (hmz) #294 1 P 0.00001 (2/243,800) M 11.0 5.0 Excessive adiposity, aggressive behavior, polydactyl 61 57 10 BBS2 c.1759_1762del/p.P587Sfs*10 (hmz) #318 1 P 0 M 9.0 6.2 Excessive adiposity, intellectual disability, polydactyl 27 19 10 BBS5 c.668_671del/p.E223Afs*14 (hmz) #316 1 P 0 F 10.3 5.6 Excessive adiposity, bowlegs, delayed milestones, poor vision, recurrent tonsillitis 14 86 11 BBS5 c.2T>A/p.? (hmz) #198 1 P 0.000012 (3/249,784) M 0.9 4.5 Excessive adiposity, polydactyl, recurrent RTI 16 11 1 BBS5 c.206T>G/p.V69G (hmz) #335 1 LP† 0 M 14 4.1 Excessive adiposity, poor vision, intellectual disability, polydactyl 11 21 11 BBS9 c.662A>G/p.E221G (htz), c.635T>C/p.F212S (htz) #128 1 LP 0 F 2.6 3.3 Excessive adiposity, polydactyl, recurrent RTI 14 25 9 BBS9 c.400del/p.T134Qfs*5 (hmz) #131 1 P 0 M 1.5 9.4 Excessive adiposity, polydactyl 15 17 NA BBS10 c.271dup/p.C91Lfs*5 (hmz) #114, #73 2 P 0 M 1.1 (#114)
8.8 (#73)4.9 (#114)
4.2 (#73)Excessive adiposity, polydactyl 6 (#114)
42 (#73)3 (#114)
4 (#73)NA BBS10 c.257T>C/p.F86S(hmz) #214 1 LP 0 M 0.6 4.3 Excessive adiposity 7 10 14 MKKS c.775del/p.T259Lfs*21(hmz) #275, #258, #339 3 P 0.00004 (11/245,790) F 1.3 (#258)
13 (#339)10.8 (#258)
2.6 (#339)Delayed milestones; polydactyl: #258; sleep apnea: #339; poor vision in dark 25 ± 5 20 ± 5 12 ± 1 ALMS1 c.4937C>A/p.S1646* (hmz) #139 1 P 0.000004 (1/245,290) M 2.5 6.2 Excessive adiposity 10 48 12 ALMS1 c.8008C>T/p.R2670* (hmz) #140 1 P 0 M 1.9 5.8 Excessive adiposity 8 39 17 ALMS1 c.7436C>G/p.S2479* (hmz) #221 1 P 0.00082 (2/245,262) M 1.1 5.7 Anemia, poor vision 7 36 14 ALMS1 c.10975C>T/p.R3659* (hmz) #338 1 P 0.000004 (1/245,694) M 2.0 8.6 Delayed milestones, poor vision 12 59 1 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).
- Table 2
Genetic and clinical data of probands with CNVs causing obesity and/or intellectual disability
Proband ID CNV Genomic interval (hg38) Gene(s) Size (kb) gnomAD region MAF Size Patho-genicity Gene or CNV- associated disorder Age (years) Sex BMI SDS for age Phenotype (other than obesity) Additional pathogenic obesity-associated variants Leptin (ng/mL) Insulin (μIU/mL) Cortisol (μg/dL) #234 1q42.12 loss hmz chr1:224923245–225051803 DNAH14 128.56 0 VUS Panventriculomegaly (CNV del), intellectual disability, hydrops fetalis, nonimmune 2.4 F 9.4 Slow learner, intellectual disability 10 8 109 #238 1p31.3 loss hmz chr1:65532214–65592881 LEPR 60.67 0 P Morbid obesity 0.8 F 9.1 38 26 12 #263 1p31.3 loss hmz chr1:65592634–65637041 LEPR 44.41 0 P Morbid obesity 1.8 F 8.4 Delayed milestones, mental retardation 27 46 13 7q31.1 loss htz chr7:111337755–111407620 IMMP2L 69.87 chr7:111209525–111532640 0.00004656 323 kb VUS Autism, epilepsy, intellectual disability, multiple congenital abnormalities (CNV loss), neurodevelopmental disorder (CNV dup) #343 1q43 loss htz chr1:240207914–240208747 FMN2 0.83 0 P Intellectual disability, mental retardation, short stature, premature ovarian failure (CNV), intellectual disability 2.1 F 6.6 Delayed milestones 117 106 11 7q31.1 loss htz chr7:111180340–111569415 IMMP2L 389.08 0 P Autism, epilepsy, intellectual disability, multiple congenital abnormalities (CNV loss), neurodevelopmental disorder (CNV dup) #304 10q21.3 loss htz chr10:66402469–66676594 CTNNA3 274.13 0 VUS Autism spectrum disorder (CNV), cardiomyopathy 3 M 7 NA 29 25 10 #334 10q25.3 loss htz chr10:115799104–116272282 ATRNL1. GFRA1 473.18 0 VUS ATRNL1: cognitive impairment, autism, dysmorphic features (CNV). GFRA1: Hirschsprung disease (CNV), central hypoventilation syndrome 2.7 F 5 Delayed milestones 22 19 5 #299 12p13.31 loss htz chr12:9192171–9208382 PZP 16.21 chr12:9172788–9215201 0.00004656 42.4 kb VUS Autism spectrum disorder, congenital heart disease, neurodevelopmental disorder, breast cancer early onset 15 F 4 Metrorrhagia, severe body ache 40 23 12 #354 12q24.33 loss htz chr12:133210742–133234403 ZNF268. ANHX 23.66 0 VUS ZNF268: autism spectrum disorder, congenital heart disease 0.7 M 1.6 Frequent diarrhea LEPR (c.2396–2A>G) 6 19 15 7q22.2 loss htz chr7:101039237–101041145 MUC17 1.91 chr7:101034793–101041958 0.0005203 7.17 kb VUS Autism spectrum disorder #271 14q11.2 loss htz chr14:20350503–20357181 PARP2 6.68 0 VUS Schizophrenia, prostate cancer, breast cancer 3.1 M 6 Slow learner 8 11 19 #339 16p13.3 loss htz chr16:4959295–4992063 SEC14L5 32.77 chr16:4958364–5031681 0.00004656 73.3 kb VUS Autism spectrum disorder 13 F 5.5 Intellectual disability, delayed puberty, polydactyly MKKS (c.775del. p.T259Lfs*21) 14 32 13 #347 16p12.2 loss htz chr16:21510262–21728466 OTOA. METTL9. IGSF6 218.21 0 P OTOA: autism spectrum disorder, hearing loss (CNV). METTL9: cognitive impairment 4 F 4.0 Delayed milestones, memory loss 4 25 14 #294 18p11.31 loss htz chr18:4233040–4421599 DLGAP1. DLGAP1-AS5 188.56 0 VUS DLGAP1: obsessive-compulsive disorder (CNV), schizophrenia, autism spectrum disorder, developmental disorder 11 M 5 Poor vision, aggressive behavior BBS2 (c.116A>G. p.K39R) 61 57 10 #303 19p13.2 loss htz chr19:8904672–8906876 MUC16 2.21 chr19:8688936–9141019 0.00004656 453 kb VUS Autism spectrum disorder 0.4 M 5 NA 5 21 10 #247 19p13.2 loss htz chr19:12398272–12431993 ZNF443. ZNF799 33.72 chr19:12386649–12433971 0.0002328 47.3 kb VUS ZNF799: autism spectrum disorder, Tourette syndrome 6.5 M 4.5 NA 10 10 17 #244 2q11.2 loss htz chr2:97077521–97244014 FAHD2B. ANKRD36 166.49 0 VUS ANKRD36: autism spectrum disorder, psychosis 22 M PWS-like features, no facial hair 31 16 16 #270 2q32.1 loss htz chr2:183023784–184276709 NCKAP1. DUSP19. NUP35 1,252.93 0 VUS NCKAP1: autism spectrum disorder 4.1 M 8.4 Sleep apnea, aggressive behavior, recurrent RTI 22 61 7 #215 2q37.3 loss htz chr2:239281474–239282694 HDAC4 1.22 chr2:239281331–239282793 0.001498 1.46 kb VUS Brachydactyly, mental retardation 1.1 M 6.5 Sleep apnea, gastric problems 23 83 14 #219 20p12.1 loss htz chr20:14867224–15009042 MACROD2 141.82 chr20:14677820–15136935 0.00004656 459 kb VUS Early-onset obesity (CNV dup); Kabuki syndrome, ADHD, schizophrenia (CNV loss) 0.8 M 8.7 Slow learner 18 18 7 17q24.2 loss htz chr17:68145129–68515603 ARSG. AMZ2. PRKAR1A. WIPI1. SLC16A6 370.48 0 VUS ARSG: Usher syndrome, neurodevelopmental disorder. PRKAR1A: Carney complex (CNV) #224 22q12.3 loss htz chr22:32247382–32255353 SLC5A4 7.97 0 VUS ADHD 9.5 M 4.1 Asthma, mild intellectual disability 12 12 6 7q31.1 loss htz chr7:111407385–111596185 IMMP2L 188.8 chr7:111380309–111597224 0.00004656 217 kb P Autism, epilepsy, intellectual disability, multiple congenital abnormalities (CNV loss), neurodevelopmental disorder (CNV dup) #277 6p22.3 loss htz chr6:17754387–17781333 KIF13A 26.95 0 VUS Autism spectrum disorder 0.6 F 7 Wakes up at night demanding food 28 9 28 4q35.1-q35.2gain chr4:186017165–186210660 TLR3. FAM149A. CYP4V2 193.5 0 VUS TLR3: herpes simplex encephalitis/encephalopathy; immunodeficiency. FAM149A: pulmonary arterial hypertension. CYP4V2: Bietti crystalline corneoretinal dystrophy (CNV loss); retinitis pigmentosa #298 6p22.3 loss htz chr6:17893182–18021242 KIF13A 128.06 0 VUS Autism spectrum disorder 11 F 3.8 Intellectual disability, hypothyroidism 25 31 11 15q21.1 gain chr15:45106503–45178335 DUOX2. DUOXA1. DUOX1. SHF 71.83 0 VUS DUOX2: hypothyroidism.
DUOXA1: schizophrenia, hydrops fetalis.
DUOX1: intellectual disability, hypothyroidism#250 8p22 loss htz chr8:16098745–16164282 MSR1 65.54 chr8:16087944–16166408 0.001723 78.5 kb VUS Schizophrenia (CNV loss), Barrett esophagus/esophageal adenocarcinoma, prostate cancer 0.9 F 3.7 Mild intellectual disability, slow movements 7 2 10 #316 10q26.13 gain chr10:121503759–121870059 FGFR2. ATE1 366.3 0 VUS FGFR2: Apert syndrome (CNV dup), craniosynostosis.
ATE1: hearing impairment, tinnitus, atrioventricular septum defect10.3 F 5.5 Slow learner, bowlegs, poor vision BBS5 (c.668_671del. p.E223Afs*14) 14 86 11 #333 4p16.3 loss htz chr4:3444014–3448310 HGFAC 4.3 0 VUS Autism spectrum disorder 19 M BMI: 39 Delayed milestones 45 102 14 #39 15q11.2-q13.1 loss htz chr15:23235221–26108349 (hg19) MKRN3. MAGEL2. NDN. NPAP1. SNRPN. SNURF. UBE3A. ATP10A 2,873.1 0 P 15q11.2-q13.1 loss CNV, feeding difficulties in infancy, hypogonadism, intellectual disability, muscular hypotonia, truncal obesity, schizophrenia 6.1 F 5.2 Atrophied uterus and ovaries 130 36 8 #87 15q11.2-q13.1 loss htz chr15:23996462–28544359 (hg19) NPAP1. SNRPN. SNURF. UBE3A. ATP10A. GABRB3. GABRA5. GABRG3. OCA2. HERC2 4,547.9 0 P 15q11.2-q13.1 loss CNV, feeding difficulties in infancy, hypogonadism, intellectual disability, muscular hypotonia, truncal obesity, schizophrenia 22 F BMI: 43 No menarche, moderate intellectual disability 28 19 7 #320 15q11.2-q13.1 loss htz chr15:22781870–26561186 NIPA1. NIPA2. CYFIP1. TUBGCP5. GOLGA6L1. LOC102723534. GOLGA8S. MKRN3. MAGEL2. NDN. LOC105370733. NPAP1. SNRPN. SNURF. UBE3A. ATP10A. GABRB3 3,779.320 0 P 15q11.2-q13.1 loss CNV, feeding difficulties in infancy, hypogonadism, intellectual disability, muscular hypotonia, truncal obesity, schizophrenia 4.8 M 6.0 PWS-like features, intellectual disability 12 28 7 5q23.2 gain chr5:127447531–127539157 MEGF10. PRRC1 91.63 chr5:127045431–127965806 0.00004902 920 kb VUS MEGF10: minicore myopathy, congenital myopathy, muscle weakness #282 16p11.2 loss htz chr16:29581926–30231884 SPN. QPRT. C16orf54. ZG16. KIF22. MAZ. PRRT2. PAGR1. MVP. CDIPT. SEZ6L2. ASPHD1. KCTD13. TMEM219. TAOK2. HIRIP3. INO80E. DOC2A. C16orf92. FAM57B. ALDOA. PPP4C. TBX6. YPEL3. GDPD3. MAPK3. CORO1A. BOLA2B. SLX1A. SULT1A3. NPIPB13 649.96 0 P 16p11.2 loss CNV, severe obesity, autism 8 F 3.2 Slow learner, delayed milestones 18 7 16 #338 11p12 gain chr11:36592557–36957106 RAG2. C11orf74 364.55 0 VUS RAG2: immunodeficiency (CNV), Omenn syndrome 2 M 8.6 Poor vision, delayed milestones ALMS1 (c.10972C>T. p.R3658*) 12 60 1 #315 11q23.3 gain chr11:118077018–118152698 TMPRSS4. SCN4B 75.68 chr11:118076058–118161781 0.00004902 85.7 kb VUS TMPRSS4: cerebral atrophy, autosomal recessive. SCN4B: atrial fibrillation 2.6 F 7.2 NA 15 25 10 #313 16p13.3 gain chr16:43545–176835 POLR3K. SNRNP25. MPG 133.29 0 VUS POLR3K: Hypomyelinating leukodystrophy.
MPG: schizophrenia, colorectal cancer5.2 F 5.5 Intellectual disability, recurrent RTI 11 50 13 #290 18q21.33 gain chr18:63641736–63659552 SERPINB3. SERPINB4 17.82 0 VUS SERPINB3: liver cirrhosis.
SERPINB4: diabetes MODY, autism spectrum disorder17 F Secondary amenorrhea 31 96 11 #321 19q13.43 gain chr19:57477251–57491801 ZNF772. ZNF419 14.55 chr19:57461161–57532262 0.00004902 71 kb VUS ZNF419: autism spectrum disorder 0.6 F 7.4 NA LEPR (c.2396–1G>T) 26 17 13 #307 2p11.2 gain chr2:85302449–85322813 TCF7L1. TGOLN2 20.36 0 VUS TCF7L1: glaucoma, primary congenital (CNV), autism 6.0 M 5.2 Intellectual disability 17 34 11 4q35.1-q35.2 gain chr4:186017165–186210660 TLR3. FAM149A. CYP4V2 193.5 chr4:185990671–186121496 0.00009804 131 kb VUS TLR3: herpes simplex encephalitis/encephalopathy, influenza-associated.
CYP4V2: Bietti crystalline corneoretinal dystrophy, retinitis pigmentosa.
TLR3: inflammatory bowel disease, schizophrenia#319 2q14.2 gain chr2:119195166–119810001 STEAP3. DBI. TMEM37. CFAP221. TMEM177. PTPN4 614.84 0 VUS STEAP3: hypochromic anemia.
PTPN4: Rett-like syndrome (CNV loss), autism spectrum disorder, neurodevelopmental disorder5 M 4.4 Delay in mental age, aggressive behavior 9 122 11 #285 21q11.2 gain chr21:13251123–14109107 POTED. LIPI 857.99 0 VUS LIPI: hypertriglyceridemia 11 M 3.7 NA 30 41 23 #275 21q22.3 gain chr21:42259283–42296415 ABCG1 37.13 0 VUS Abnormal HDL cholesterol, autism spectrum disorder, heart disease F NA MKKS (c.775del.p.T259Lfs*21) 29 14 9 #342 22q11.22 gain chr22:21955538–22110518 TOP3B 154.98 0 P Mild mental retardation, generalized overgrowth (CNV dup), intellectual disability, schizophrenia 1.8 F 8.8 Delayed milestones LEP (c.-29+1G>C) 2 19 15 3q29 gain chr3:197791254–197875785 LRCH3 84.53 chr3:197791715–197915689 0.00009804124 kb VUS Neurodevelopmental disorder #266 22q11.22 gain chr22:21955538–22110518 TOP3B 154.98 0 P Mild mental retardation, generalized overgrowth (CNV dup), intellectual disability, schizophrenia 4.4 F 6.1 NA 23 26 8 #329 22q11.22 gain chr22:21957088–22215308 TOP3B 258.22 0 P Mild mental retardation, generalized overgrowth (CNV dup), intellectual disability, schizophrenia 2.8 F 8.3 NA 19 26 8 #205 4p13 gain chr4:42806238–43454858 GRXCR1 648.62 0 VUS Deafness, dizziness 1.6 M 5.3 NA 5 9 5 #252 5q31.3 gain chr5:141332929–141341211 PCDHGA1. PCDHGA2 8.28 0 VUS PCDHGA2: Cardiovascular malformation M #332 5q32 gain chr5:149860860–149886410 PDE6A 25.55 chr5:149629797–150001191 0.00009804 371 kb VUS Retinitis pigmentosa, Leber congenital amaurosis 16 M 3.2 Rudimentary external genitalia, autistic 35 27 10 ADHD, attention deficit hyperactivity disorder; chr, chromosome; del, deletion; dup, duplicate; hmz, homozygous; htz, heterozygous; MAF, minor allele frequency; MODY, maturity-onset diabetes of the young; NA, not available; P, pathogenic; RTI, respiratory tract infection.
In this Issue
July 2020, 69(7)
Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan
