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  1. NGS Panel – Genetic Testing for Kallmann Syndrome and Hypogonadotropic Hypogonadism

Kallmann Syndrome and Hypogonadotropic Hypogonadism

August 22, 2017

Inheritance pattern

Autosomal recessive, autosomal dominant, X-linked


Clinical features

Kallmann syndrome (KS) is a developmental genetic disorder characterized by delayed or absent puberty and impaired sense of smell and it belongs to isolated gonadotropin-releasing hormone deficiencies. Deficient hypothalamic gonadotropin-releasing hormone (GnRH) secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.

Incidence of Kallmann syndrome was estimated to be 1:30,000 in males and 1:125,000 in females in Finland with the male-to-female ratio of nearly 4:1 1.

Patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism may not experience puberty or may experience incomplete puberty and have symptoms associated with hypogonadism. For men, these symptoms include decreased libido, erectile dysfunction, decreased muscle strength, and diminished aggressiveness and drive 2, 3. For women, symptoms include amenorrhea and dyspareunia. Family members of patients with idiopathic hypogonadotropic hypogonadism may have a history of delayed, although otherwise normal, puberty 2, 3.

The impaired olfactory function in Kallmann syndrome can be either hyposmia or complete anosmia 2, 3. Most individuals with impaired sense of smell are otherwise asymptomatic. Isolated gonadotropine deficiency is associated with a normal sense of smell (“normosmic”) in approximately 40% of affected individuals and with an impaired sense of smell (Kallmann syndrome) in approximately 60% of affected cases 2, 3.

Laboratory findings of Kallmann syndrome and hypogonadotropic hypogonadism include reduced levels of testosterone in males and estradiol in females, as well as very low serum concentrations of LH (luteinizing hormone) and FSH (follicle stimulating hormone). Levels of other anterior pituitary hormones are typically normal.

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABCB11 603201 progressive familial intrahepatic cholestasis type 2; benign recurrent intrahepatic cholestasis type 2 AR 24
ABCB4 171060 gallbladder disease type 1; progressive familial intrahepatic cholestasis type 3; Cholestasis, intrahepatic, of pregnancy, 3 AD, AR 31
ABCC2 601107 Dubin-Johnson syndrome AR 19
ACTN4 604638 Glomerulosclerosis, focal segmental, 1 AD 17
ACVR2B 602730 Heterotaxy, visceral, 4, autosomal 1
AGPS 603051 rhizomelic chondrodysplasia punctata type 3 AR 7
AHI1 608894 Joubert syndrome 3 AR 16
AIPL1 604392 Leber congenital amaurosis 4 AD, AR 8
AKR1D1 604741 Bile acid synthesis defect, congenital, 2 AR 1
ALDOB 612724 hereditary fructose intolerance AR 7
ALG8 608103 congenital disorder of glycosylation type 1h AD, AR 2
ALPL 171760 adult hypophosphatasia; infantile hypophosphatasia; childhood-onset hypophosphatasia AD, AR 40
ANKH 605145 Chondrocalcinosis 2; Craniometaphyseal dysplasia AD 3
ANKS6 615370 nephronophthisis 16 AR 4
ANO5 608662 gnathodiaphyseal dysplasia; limb-girdle muscular dystrophy type 2L AD, AR 8
ANOS1 300836 Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) XLR 8
AP2S1 602242 Hypocalciuric hypercalcemia, familial, type III AD 4
ARHGAP31 610911 Adams-Oliver syndrome 1 AD 12
ARHGDIA 601925 Nephrotic syndrome, type 8 AR 1
ARL13B 608922 Joubert syndrome 8 AR 2
ARL6 608845 Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 AR, DiR 6
ARMC4 615408 primary ciliary dyskinesia, 23 AR 2
ARSL 300180 Chondrodysplasia punctata, X-linked recessive XLR 3
ATP6V0A4 605239 distal renal tubular acidosis AR 8
ATP6V1B1 192132 Renal tubular acidosis with deafness AR 9
ATP8B1 602397 Cholestasis, intrahepatic, of pregnancy, 1; Cholestasis, Progressive Familial Intrahepatic, 1; Cholestasis, Benign Recurrent Intrahepatic, 1 AD, AR 21
ATR 601215 Seckel syndrome 1; ?Cutaneous telangiectasia and cancer syndrome, familial AD, AR 15
B9D1 614144 Meckel Syndrome, Type 9 AR 11
B9D2 611951 Meckel syndrome 10 AR 4
BBS1 209901 Bardet-Biedl syndrome type 1 AR, DiR 14
BBS10 610148 Bardet-Biedl syndrome type 10 AR 11
BBS12 610683 Bardet-Biedl syndrome type 12 AR 8
BBS2 606151 Bardet-Biedl syndrome type 2; retinitis pigmentosa type 74 AR 16
BBS4 600374 Bardet-Biedl syndrome 4 AR 11
BBS5 603650 Bardet-Biedl syndrome 5 AR 27
BBS7 607590 Bardet-Biedl syndrome type 7 AR 17
BBS9 607968 Bardet-Biedl syndrome type 9 AR 24
BCS1L 603647 Mitochondrial complex III deficiency, nuclear type 1; Leigh syndrome; Bjornstad syndrome; GRACILE syndrome AR, M 6
BICC1 614295 Renal dysplasia, cystic, susceptibility to AD 29
BMP1 112264 osteogenesis imperfecta type 13 AR 9
BMPR1B 603248 Brachydactyly type A2; Chondrodysplasia, Acromesomelic, With Genital Anomalies AD, AR 0
BSND 606412 Bartter Syndrome type 4A AR 5
C8orf37 614477 Cone-rod dystrophy 16; Bardet-Biedl syndrome type 21 AR 3
CA2 611492 Osteopetrosis, autosomal recessive 3, with renal tubular acidosis AR 8
CABP4 608965 Night blindness, congenital stationary (incomplete), 2B, autosomal recessive AR 6
CANT1 613165 Desbuquois dysplasia type 1 AR 2
CASP10 601762 Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer AD 4
CASR 601199 Hypocalciuric hypercalcemia, type I; Hyperparathyroidism, neonatal; Hypocalcemia, autosomal dominant, with Bartter syndrome; Epilepsy idiopathic generalized, susceptibility to, 8 AD, AR 13
CC2D2A 612013 COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 AR 24
CCDC103 614677 Ciliary dyskinesia, primary, 17 AR 3
CCDC114 615038 Ciliary dyskinesia, primary, 20 AR 7
CCDC151 615956 primary Ciliary dyskinesia type 30 AR 0
CCDC28B 610162 Bardet-Biedl syndrome type 1 AR, DiR 1
CCDC39 613798 Ciliary dyskinesia, primary, 14 8
CCDC40 613799 Ciliary dyskinesia, primary, 15 27
CCDC65 611088 Ciliary dyskinesia, primary, 27 AR 1
CCNO 607752 primary ciliary dyskinesia type 29 AR 3
CD2AP 604241 Glomerulosclerosis, focal segmental, 3 9
CDKN1C 600856 Beckwith-Wiedemann syndrome; IMAGE syndrome AD 14
CENPF 600236 Stromme syndrome AR 12
CENPJ 609279 primary microcephaly 6; Seckel syndrome 4 AR 13
CEP152 613529 Seckel syndrome 5; primary microcephaly 9 AR 10
CEP164 614848 nephronophthisis 15 AR 14
CEP290 610142 Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 AR 51
CEP41 610523 Joubert syndrome 15 AR 3
CEP63 614724 Seckel syndrome 6 AR 22
CFAP298 615494 primary ciliary dyskinesia type 26 AR 1
CFAP53 614759 Heterotaxy, visceral, 6, autosomal recessive AR 0
CFC1 605194 Heterotaxy, visceral, 2, autosomal AD 3
CFTR 602421 hereditary pancreatitis; Bronchiectasis with or without elevated sweat chloride type 1; cystic fibrosis; congenital bilateral absence of vas deferens AD, AR 113
CHD7 608892 CHARGE syndrome; hypogonadotropic hypogonadism-5 with or without anosmia AD 103
CHSY1 608183 AR 0
CILK1 612325 AD, AR 0
CLCN5 300008 Dent disease; Hypophosphatemic rickets; Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis; Nephrolithiasis, type I XLR 1
CLCNKA 602024 Bartter syndrome, type 4b, digenic DiR 38
CLCNKB 602023 Bartter syndrome, type 3; Bartter syndrome, type 4b, digenic AR, DiR 44
CLDN16 603959 renal hypomagnesemia type 3 AR 1
CLDN19 610036 Hypomagnesemia 5, renal, with ocular involvement AR 3
CNGA3 600053 Achromatopsia type 2 AR 2
COL10A1 120110 METAPHYSEAL CHONDRODYSPLASIA, SCHMID TYPE AD 5
COL4A1 120130 porencephaly 1; Brain small vessel disease with or without ocular anomalies; Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps; Hemorrhage, intracerebral, susceptibility to AD 71
COL4A3 120070 Alport syndrome 3, AD; benign familial hematuria benign familial; Alport syndrome, AR AD, AR 74
COL4A4 120131 benign familial hematuria benign familial; Alport syndrome, AR AD, AR 41
COL4A5 303630 Alport syndrome XLD 82
COL9A3 120270 multiple epiphyseal dysplasia type 3 AD 6
COMP 600310 Epiphyseal Dysplasia, Multiple, 1; Pseudoachondroplasia AD 10
COQ2 609825 Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 AD, AR 18
COQ6 614647 Coenzyme Q10 deficiency, primary, 6 AR 1
COQ8B 615567 Nephrotic syndrome, type 9 AR 2
COQ9 612837 Coenzyme Q10 deficiency, primary, 5 AR 12
CPLANE1 614571 oral-facial-digital syndrome 6; Joubert syndrome 17 AR 31
CRB1 604210 pigmented paravenous chorioretinal atrophy; retinitis pigmentosa type 12; Leber congenital amaurosis type 8 AD, AR 15
CRELD1 607170 Atrioventricular septal defect, partial, with heterotaxy syndrome AD 6
CRTAP 605497 osteogenesis imperfecta type 7 AR 8
CRX 602225 Cone-rod retinal dystrophy-2; Leber congenital amaurosis 7 AD 6
CSPP1 611654 Joubert syndrome 21 AR 11
CTNS 606272 ocular nonnephropathic cystinosis; cystinosis; late-onset juvenile or adolescent nephropathic cystinosis AR 12
CUBN 602997 megaloblastic anemia 1 AR 46
CUL3 603136 Pseudohypoaldosteronism, type IIE AD 2
CYP7B1 603711 spastic paraplegia 5A AR 17
DDR2 191311 Spondylometaepiphyseal dysplasia, short limb-hand type AD, AR 3
DGKE 601440 Nephrotic syndrome, type 7 AR 27
DGUOK 601465 mitochondrial DNA depletion syndrome 3 AR 8
DHCR7 602858 Smith-Lemli-Opitz syndrome AR 9
DMP1 600980 Hypophosphatemic Rickets, Autosomal Recessive, 1 AR 1
DNAAF1 613190 Ciliary dyskinesia, primary, 13 AR 9
DNAAF2 612517 Ciliary dyskinesia, primary, 10 6
DNAAF3 614566 Ciliary dyskinesia, primary, 2 AR 2
DNAAF4 608706 Ciliary dyskinesia, primary, 25 AD, AR 0
DNAAF5 614864 Ciliary dyskinesia, primary, 18 AR 12
DNAH11 603339 primary ciliary dyskinesia type 7, with or without situs inversus AR 56
DNAH5 603335 primary ciliary dyskinesia type 3, with or without situs inversus 38
DNAI1 604366 primary ciliary dyskinesia type 1, with or without situs inversus AR 4
DNAI2 605483 primary ciliary dyskinesia type 9, with or without situs inversus 5
DNAL1 610062 Ciliary dyskinesia, primary, 16 AR 2
DRC1 615288 primary ciliary dyskinesia, 21 AR 2
DUSP6 602748 Hypogonadotropic hypogonadism 19 with or without anosmia AD 0
DYM 607461 Dyggve-Melchior-Clausen disease AR 5
DYNC2H1 603297 short-rib thoracic dysplasia-3 with or without polydactyly AR, DiR 10
DYNC2I1 615462 Short-rib thoracic dysplasia 8 with or without polydactyly AR 3
DYNC2I2 613363 Short-rib thoracic dysplasia 11 with or without polydactyly AR 3
EBP 300205 MEND syndrome; Chondrodysplasia punctata, X-linked dominant XLD, XLR 2
EIF2AK3 604032 Wolcott-Rallison syndrome AR 2
ENPP1 173335 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Arterial calcification, generalized, of infancy, 1; OBESITY; Hypophosphatemic rickets, autosomal recessive, 2; Cole disease AD, AR 8
ESCO2 609353 Roberts syndrome AR 12
EVC 604831 Weyers acrofacial dysostosis; Ellis-van Creveld syndrome AD, AR 9
EVC2 607261 Weyers acrofacial dysostosis; Ellis-van Creveld syndrome AD, AR 5
FAH 613871 tyrosinemia type 1 AR 17
FAS 134637 Autoimmune lymphoproliferative syndrome AD 4
FASLG 134638 Lung Cancer; Autoimmune lymphoproliferative syndrome AD 1
FEZF1 613301 AR 0
FGF17 603725 Hypogonadotropic hypogonadism 20 with or without anosmia AD 0
FGF23 605380 Hypophosphatemic rickets, autosomal dominant AD, AR 6
FGF8 600483 hypogonadotropic hypogonadism 6 with or without anosmia AD 13
FGFR1 136350 Craniofacial-skeletal-dermatologic dysplasia; Jackson-Weiss syndrome; hypogonadotropic hypogonadism-2 with or without anosmia; Osteoglophonic dysplasia; Hartsfield syndrome AD 24
FKBP10 607063 Bruck syndrome 1; osteogenesis imperfecta type 11 AR 8
FLNB 603381 Atelosteogenesis, type i; Atelosteogenesis, type iii; Boomerang dysplasia; Larsen syndrome; Spondylocarpotarsal synostosis syndrome AD, AR 23
FLRT3 604808 AD 0
FSHB 136530 AR 0
FXYD2 601814 Hypomagnesemia-2, renal AD 2
GDF1 602880 Right atrial isomerism; Transposition of the great arteries, dextro-looped 3 AD, AR 5
GDF5 601146 Brachydactyly type A2; Brachydactyly type C; Grebe type chondrodysplasia; Hunter-Thompson type of acromesomelic dysplasia; Du Pan syndrome; multiple synostoses syndrome type 2; susceptibility to osteoarthritis type 5; brachydactyly type A1; proximal symphalangism type 1B AD, AR 1
GFM1 606639 Combined oxidative phosphorylation deficiency 1 AR 10
GHR 600946 familial hypercholesterolemia; Laron syndrome; Increased responsiveness to growth hormone AD, AR 11
GLA 300644 Fabry disease; Fabry disease, atypical cardiac variant XL 630
GLI2 165230 holoprosencephaly 9; Culler-Jones syndrome AD 19
GLI3 165240 Pallister-Hall syndrome; Polydactyly, postaxial, types A1 and B; Preaxial polydactyly type IV; Greig cephalopolysyndactyly syndrome AD 30
GLIS2 608539 nephronophthisis 7 0
GNA11 139313 Hypocalciuric hypercalcemia, familial, type ii; Hypocalcemia, autosomal dominant 2 AD 1
GNAS 139320 Pseudohypoparathyroidism Ia; Osseous heteroplasia, progressive; McCune-Albright syndrome, somatic, mosaic; ACTH-independent macronodular adrenal hyperplasia; Pseudohypoparathyroidism type Ib; Pseudohypoparathyroidism Ic; Pseudopseudohypoparathyroidism AD 23
GNPAT 602744 rhizomelic chondrodysplasia punctata type 2 AR 6
GNRH1 152760 hypogonadotropic hypogonadism 12 with or without anosmia AR 4
GNRHR 138850 hypogonadotropic hypogonadism 7 with or without anosmia AR 6
GUCY2D 600179 Leber congenital amaurosis type 1; cone-rod dystrophy type 6 AD, AR 18
HAMP 606464 Hemochromatosis, type 2B AR 0
HESX1 601802 Septooptic dysplasia AD, AR 0
HEXA 606869 Tay-Sachs disease/ GM2-gangliosidosis AR 25
HFE 613609 Alzheimer Disease; hepatoerythropoietic porphyria; variegate porphyria; hemochromatosis type 1; susceptibility to microvascular complications of diabetes type 7; Transferrin serum level QTL2 AD, AR 11
HNF1B 189907 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic AD 14
HNF4A 600281 MODY type 1; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young AD 11
HS6ST1 604846 hypogonadotropic hypogonadism 15 with or without anosmia AD 2
HSD11B2 614232 apparent mineralocorticoid excess AR 6
HSD3B7 607764 Bile acid synthesis defect, congenital, 1 AR 7
HSPG2 142461 Silverman-Handmaker type of dyssegmental dysplasia; Schwartz-Jampel syndrome AR 30
HYDIN 610812 primary ciliary dyskinesia type 5 AR 131
HYLS1 610693 Hydrolethalus syndrome AR 2
IFITM5 614757 osteogenesis imperfecta type 5 AD 7
IFT122 606045 Cranioectodermal dysplasia 1 AR 3
IFT140 614620 Mainzer-Saldino syndrome; retinitis pigmentosa type 80 AR 1
IFT172 607386 Short-rib thoracic dysplasia 10 with or without polydactyly AR 4
IFT27 615870 Bardet-Biedl syndrome 19 AR 0
IFT43 614068 Cranioectodermal dysplasia 3 AR 2
IFT80 611177 AR 0
IL17RD 606807 Hypogonadotropic hypogonadism type 18 with or without anosmia AD, AR, DiD 2
IMPDH1 146690 Retinitis pigmentosa 10; Leber congenital amaurosis 11 AD 8
INF2 610982 Focal Segmental Glomerulosclerosis 5; intermediate type E Charcot-Marie-Tooth AD 8
INPP5E 613037 Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis AR 18
INPPL1 600829 Opsismodysplasia AR 6
INVS 243305 nephronophthisis 2 AR 9
IQCB1 609237 Senior-Loken syndrome 5 AR 19
ITGA3 605025 Congenital interstitial lung disease with nephrotic syndrome and epidermolysis bullosa AR 11
JAG1 601920 Alagille syndrome; Tetralogy of Fallot AD 43
KCNJ1 600359 Bartter syndrome, type 2 AR 6
KCNJ10 602208 autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance AR 7
KCNJ13 603208 AD, AR 0
KCNJ5 600734 Long QT syndrome 13 AD 3
KIF7 611254 Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 AR 25
KISS1 603286 hypogonadotropic hypogonadism 13 with or without anosmia AR 3
KISS1R 604161 Precocious puberty, central, 1; hypogonadotropic hypogonadism 8 with or without anosmia AD, AR 6
KLHL3 605775 Pseudohypoaldosteronism, type IID AD, AR 15
LAMB2 150325 Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalities AR 19
LBR 600024 Pelger-Huet anomaly; Greenberg skeletal dysplasia AD, AR 2
LCA5 611408 Leber congenital amaurosis type 5 AR 3
LCT 603202 AR 0
LEFTY2 601877 2
LEP 164160 Leptin deficiency AR 3
LEPR 601007 Morbid obesity due to leptin receptor deficiency AR 1
LHB 152780 Hypogonadotropic hypogonadism 23 with or without anosmia AR 1
LHX3 600577 Pituitary hormone deficiency, combined, 3 AR 0
LHX4 602146 Pituitary hormone deficiency, combined, 4 AD 1
LIFR 151443 Stuve-Wiedemann syndrome AR 14
LMX1B 602575 Nail-patella syndrome AD 10
LRAT 604863 Leber congenital amaurosis 14 AR 0
LRP5 603506 Hyperostosis Corticalis Generalisata, Benign Form Of Worth, With Torus Palatinus; OSTEOPOROSIS; Osteoporosis-pseudoglioma syndrome; Exudative vitreoretinopathy 4; Bone Mineral Density Quantitative Trait Locus 1; autosomal dominant osteopetrosis type 1; van Buchem disease, type 2 AD, AR 35
LRRC6 614930 Ciliary dyskinesia, primary, 19 AR 2
LZTFL1 606568 Bardet-Biedl syndrome 17 AR 5
MAGI2 606382 nephrotic syndrome type 15 AR 18
MATN3 602109 Epiphyseal dysplasia, multiple, 5 AD, AR 1
MCEE 608419 Methylmalonyl-coa epimerase deficiency AR 4
MERTK 604705 Retinitis pigmentosa 38 AR 24
MKKS 604896 McKusick-Kaufman syndrome; Bardet-Biedl syndrome type 6 AR 6
MKS1 609883 Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 AR 7
MMAA 607481 methylmalonic aciduria (MMA) of the cblA complementation type AR 7
MMAB 607568 methylmalonic aciduria (MMA) of the cblB complementation type AR 7
MMADHC 611935 methylmalonic aciduria (MMA) of the cblD complementation type AR 5
MMP13 600108 Metaphyseal dysplasia, Spahr type; Spondyloepimetaphyseal dysplasia, Missouri type AD, AR 9
MMP21 608416 Heterotaxy, visceral, 7, autosomal AR 5
MMP9 120361 Metaphyseal anadysplasia 2 2
MMUT 609058 complete deficiency of methylmalonyl-CoA mutase AR 30
MPV17 137960 mitochondrial DNA depletion syndrome type 6 AR 7
MYH9 160775 Fechtner syndrome; Macrothrombocytopenia and progressive sensorineural deafness; May-Hegglin anomaly; Sebastian syndrome; deafness type 17 AD 8
MYO7A 276903 Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 AD, AR 31
NBAS 608025 Short stature, optic nerve atrophy, and Pelger-Huet anomaly; Infantile liver failure syndrome type 2 AR 9
NEK1 604588 Short-rib thoracic dysplasia 6 with or without polydactyly AD, AR, DiR 2
NEK8 609799 nephronophthisis 9; Renal-hepatic-pancreatic dysplasia 2 AR 2
NEUROG3 604882 Diarrhea 4, malabsorptive, congenital AR 2
NKX2-5 600584 Atrial Septal Defect 7 With Or Without Atrioventricular Conduction Defects; Tetralogy of Fallot; Conotruncal Heart Malformations; Hypothyroidism, Congenital, Nongoitrous, 5; Ventricular septal defect 3; Hypoplastic left heart syndrome 2 AD 3
NKX3-2 602183 Spondylo-megaepiphyseal-metaphyseal dysplasia AR 0
NME8 607421 Ciliary dyskinesia, primary, 6 AR 10
NMNAT1 608700 Leber congenital amaurosis 9 AR 2
NODAL 601265 Heterotaxy, visceral, 5, autosomal AD 2
NOG 602991 proximal symphalangism 1A AD 0
NOTCH2 600275 Hajdu-Cheney syndrome; Alagille syndrome 2 AD 116
NPC1 607623 Niemann-Pick disease type C/D AR 249
NPC2 601015 Niemann-Pick disease type C2 AR 17
NPHP1 607100 nephronophthisis 1; Joubert syndrome 4 AR 19
NPHP3 608002 Renal-hepatic-pancreatic dysplasia 1; Meckel syndrome 7; nephronophthisis 3 AR 16
NPHP4 607215 nephronophthisis 4 AR 14
NPHS1 602716 nephrotic syndrome type 1 AR 31
NPHS2 604766 nephrotic syndrome type 2 AR 12
NR0B1 300473 46XY sex reversal 2, dosage-sensitive; Adrenal hypoplasia, congenital, with hypogonadotropic hypogonadism XL, XLR 2
NR0B2 604630 OBESITY AD, AR 0
NR3C2 600983 Pseudohypoaldosteronism type I, autosomal dominant AD 7
NSDHL 300275 CK syndrome; CHILD syndrome XLD, XLR 4
NSMF 608137 hypogonadotropic hypogonadism 9 with or without anosmia AD 1
OCRL 300535 Dent disease type 2; Lowe oculocerebrorenal syndrome XLR 13
OFD1 300170 Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 XLD, XLR 22
OTX2 600037 Microphthalmia, syndromic 5; Pituitary hormone deficiency, combined, 6 AD 2
P3H1 610339 osteogenesis imperfecta type 8 AR 5
PAX2 167409 Papillorenal syndrome AD 5
PCSK1 162150 Obesity with impaired prohormone processing AR 2
PDE6D 602676 Joubert syndrome 22 AR 1
PDSS2 610564 Coenzyme Q10 deficiency, primary, 3 AR 10
PEX1 602136 Peroxisome biogenesis disorder type 1A (Zellweger); Heimler syndrome type 1; peroxisome biogenesis disorder type 1B AR 42
PEX10 602859 peroxisome biogenesis disorder 6A (Zellweger); peroxisome biogenesis disorder 6B AR 8
PEX12 601758 peroxisome biogenesis disorder type 3B; peroxisome biogenesis disorder type 3A (Zellweger) AR 10
PEX2 170993 peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B AR 4
PEX26 608666 peroxisome biogenesis disorder type 7A (Zellweger); peroxisome biogenesis disorder 7B AR 5
PEX5 600414 peroxisome biogenesis disorder 2B (Zellweger); peroxisome biogenesis disorder 2A (Zellweger); Rhizomelic chondrodysplasia punctata, type 5 AR 15
PEX6 601498 peroxisome biogenesis disorder type 4A (Zellweger); peroxisome biogenesis disorder type 4B; Heimler syndrome type 2 AD, AR 35
PEX7 601757 Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) AR 15
PHEX 300550 X-linked dominant hypophosphatemic rickets XLD 14
PHF6 300414 Borjeson-Forssman-Lehmann syndrome XLR 5
PKD1L1 609721 Visceral heterotaxy type 8 AR 1
PKD2 173910 polycystic kidney disease type 2 AD 44
PKHD1 606702 polycystic kidney disease type 4 with or without polycystic liver disease AR 112
PLCE1 608414 Nephrotic syndrome, type 3 AR 21
PLOD2 601865 Bruck syndrome 2 AR 11
PMM2 601785 congenital disorder of glycosylation type 1a AR 3
PNPLA6 603197 Boucher-Neuhauser syndrome; spastic paraplegia 39 AR 55
POLG 174763 progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B AD, AR 50
POLR3B 614366 hypomyelinating leukodystrophy-8 AR 24
POMC 176830 OBESITY; Proopiomelanocortin Deficiency AD, AR 2
POU1F1 173110 Pituitary hormone deficiency, combined, 1 AD, AR 1
PPARG 601487 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 AD, AR 2
PPIB 123841 osteogenesis imperfecta type 9 AR 2
PRKAR1A 188830 Acrodysostosis 1 With Or Without Hormone Resistance; Carney complex, type 1; Myxoma, intracardiac; Pigmented nodular adrenocortical disease, primary, 1 AD 14
PROK2 607002 hypogonadotropic hypogonadism 4 with or without anosmia AD 4
PROKR2 607123 hypogonadotropic hypogonadism 3 with or without anosmia AD 9
PROM1 604365 Stargardt disease 4; Macular dystrophy, retinal, 2; Retinitis pigmentosa 41; Cone-rod dystrophy 12 AD, AR 27
PROP1 601538 Pituitary hormone deficiency, combined, 2 AR 3
PRPH2 179605 Retinitis punctata albescens; Patterned dystrophy of retinal pigment epithelium (macular dystrophy); Retinitis pigmentosa 7; vitelliform macular dystrophy-3; Choriodal dystrophy, central areolar 2 AD, AR 7
PTH1R 168468 primary failure of tooth eruption; Metaphyseal chondrodysplasia, Murk Jansen type; Chondrodysplasia, Blomstrand type; Eiken syndrome AD, AR 5
RBBP8 604124 Jawad syndrome / Microcephaly with mental retardation and digital anomalies; Seckel syndrome 2 AR 8
RD3 180040 Leber congenital amaurosis 12 AR 0
RDH12 608830 Leber congenital amaurosis type 13 AD, AR 9
RDH5 601617 Retinitis punctata albescens AD, AR 1
RHO 180380 Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1; Retinitis Pigmentosa 4 AD, AR 1
RLBP1 180090 Retinitis punctata albescens AD, AR 4
RMND1 614917 Combined oxidative phosphorylation deficiency 11 AR 2
ROR2 602337 Brachydactyly, type B1; Robinow syndrome, autosomal recessive AD, AR 3
RPE65 180069 Leber congenital amaurosis type 2; retinitis pigmentosa type 20 AD, AR 8
RPGRIP1 605446 Cone-rod dystrophy 13; Leber congenital amaurosis 6 AR 20
RPGRIP1L 610937 COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 AR 18
RRM2B 604712 mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 AD, AR 21
RSPH1 609314 primary ciliary dyskinesia, 24 AR 0
RSPH4A 612647 Ciliary dyskinesia, primary, 11 5
RSPH9 612648 Ciliary dyskinesia, primary, 12 2
RUNX2 600211 Cleidocranial dysplasia AD 11
SALL1 602218 Townes-Brocks syndrome AD 30
SALL4 607343 Okihiro syndrome AD 15
SBDS 607444 Shwachman-Bodian-Diamond syndrome; Aplastic Anemia AR 11
SCARB2 602257 Epilepsy, progressive myoclonic 4, with or without renal failure AR 2
SCNN1A 600228 Pseudohypoaldosteronism, type I AD, AR 14
SCNN1B 600760 Liddle syndrome; Bronchiectasis with or without elevated sweat chloride type 1; Pseudohypoaldosteronism, type I AD, AR 19
SCNN1G 600761 Pseudohypoaldosteronism, type I; Bronchiectasis with or without elevated sweat chloride 3 AD, AR 18
SDCCAG8 613524 Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 AR 12
SEMA3A 603961 hypogonadotropic hypogonadism 16 with or without anosmia AD 36
SERPINA1 107400 alpha-1 antitrypsin deficiency AR 4
SERPINF1 172860 osteogenesis imperfecta type 6 AR 2
SERPINH1 600943 Preterm premature rupture of the membranes, susceptibility to; osteogenesis imperfecta type 10 AR 3
SLC12A1 600839 Bartter syndrome type 1 AR 37
SLC12A3 600968 Gitelman syndrome AR 36
SLC25A13 603859 Citrullinemia, Type Ii, Adult-Onset; Citrullinemia, type II, neonatal-onset AR 7
SLC25A15 603861 Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 5
SLC26A2 606718 Diastrophic dysplasia; multiple epiphyseal dysplasia type 4; Atelosteogenesis type II; Achondrogenesis type IB AR 6
SLC26A3 126650 Diarrhea 1, secretory chloride, congenital AR 5
SLC2A2 138160 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi-Bickel syndrome AD, AR 31
SLC34A1 182309 Nephrolithiasis/osteoporosis, hypophosphatemic, 1; Fanconi renotubular syndrome 2; Hypercalcemia, infantile, 2 AD, AR 3
SLC34A3 609826 Hypophosphatemic rickets with hypercalciuria AR 6
SLC35D1 610804 Schneckenbecken dysplasia AR 1
SLC4A1 109270 Autosomal dominant distal renal tubular acidosis; resistance to malaria; Renal tubular acidosis, distal, with hemolytic anemia; Spherocytosis, type 4 AD, AR 9
SLC4A4 603345 Renal tubular acidosis, proximal, with ocular abnormalities AR 15
SLCO1B1 604843 Hyperbilirubinemia, Rotor type, digenic DiR 5
SLCO1B3 605495 Hyperbilirubinemia, Rotor type, digenic DiR 13
SMPD1 607608 Niemann-Pick disease type A; Niemann-Pick disease type A/B AR 87
SOX10 602229 PCWH syndrome; Waardenburg syndrome type 2E; Waardenburg syndrome, type 4C AD 20
SOX2 184429 Microphthalmia, Syndromic 3 AD 8
SOX3 313430 Mental Retardation, X-Linked, With Panhypopituitarism; Panhypopituitarism, X-linked XL 3
SOX9 608160 campomelic dysplasia AD 14
SPAG1 603395 Primary Ciliary dyskinesia type 28 AR 0
SPATA7 609868 Leber congenital amaurosis 3 13
SPINT2 605124 AR 0
SPRY4 607984 Hypogonadotropic hypogonadism 17 with or without anosmia AD 0
TAC3 162330 hypogonadotropic hypogonadism 10 with or without anosmia AR 0
TACR3 162332 hypogonadotropic hypogonadism 11 with or without anosmia AR 2
TBX5 601620 Holt-Oram syndrome AD 17
TCTN1 609863 Joubert syndrome 13 AR 5
TCTN2 613846 Meckel syndrome 8; Joubert syndrome type 24 AR 19
TCTN3 613847 oral-facial-digital syndrome 4; Joubert syndrome 18 AR 2
TFR2 604720 hemochromatosis type 3 AR 10
TJP2 607709 Hypercholanemia, familial; Cholestasis, progressive familial intrahepatic 4 AR 14
TMEM138 614459 Joubert syndrome 16 AR 1
TMEM216 613277 Meckel Syndrome type 2; Joubert syndrome type 2 AR 0
TMEM231 614949 Joubert syndrome 20; Meckel syndrome, type 11 AR 10
TMEM237 614423 Joubert syndrome 14 AR 12
TMEM67 609884 COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 AR 22
TNFRSF11B 602643 Paget disease of bone 5, juvenile-onset AR 1
TRIM32 602290 limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 AR 2
TRIP11 604505 Achondrogenesis, type IA AR 10
TRMU 610230 Deafness, Aminoglycoside-Induced; Liver Failure, Infantile, Transient AR, M 8
TRPC6 603652 Glomerulosclerosis, focal segmental, 2 AD 8
TRPS1 604386 trichorhinophalangeal syndrome 1 AD 15
TRPV4 605427 Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc AD 13
TSC1 605284 tuberous sclerosis type 1 AD 68
TSC2 191092 tuberous sclerosis-2 AD 150
TTC21B 612014 Short-rib thoracic dysplasia 4 with or without polydactyly; nephronophthisis 12 AD, AR 24
TTC8 608132 retinitis pigmentosa type 51; Bardet-Biedl syndrome type 8 AR 13
TULP1 602280 Retinitis pigmentosa 14 AR 21
UGT1A1 191740 Gilbert syndrome; Crigler-Najjar syndrome type I; familial transient neonatal hyperbilirubinemia; serum level of Bilirubin, QTL1; Crigler-Najjar syndrome type II AR 24
VHL 608537 Renal carcinoma, chromophobe, somatic; pheochromocytoma; von Hippel-Lindau disease; Erythrocytosis, familial, 2 AD, AR 10
VIPAS39 613401 Arthrogryposis, renal dysfunction, and cholestasis 2 AR 2
WDPCP 613580 Bardet-Biedl syndrome 15 AR 9
WDR11 606417 hypogonadotropic hypogonadism 14 with or without anosmia AD 12
WDR19 608151 Short-rib thoracic dysplasia 5 with or without polydactyly; nephronophthisis 13; Cranioectodermal dysplasia 4; Senior-Loken syndrome 8 AR 1
WDR35 613602 Cranioectodermal dysplasia 2 AR 2
WDR73 616144 Galloway syndrome AR 9
WNK1 605232 Neuropathy, hereditary sensory and autonomic, type II; Pseudohypoaldosteronism, type IIC AD, AR 12
WNK4 601844 Pseudohypoaldosteronism, type IIB AD 2
WNT5A 164975 Robinow syndrome, autosomal dominant AD 4
WNT7A 601570 Fuhrmann syndrome; Ulna and fibula, absence of, with sever limb deficiency AR 8
WT1 607102 Frasier syndrome; Mesothelioma, somatic; Wilms tumor, type 1; Denys-Drash syndrome; Nephrotic syndrome, type 4; Meacham syndrome AD 13
ZIC3 300265 Heterotaxy, visceral, 1, x-linked; Vacterl association, x-linked, with or without hydrocephalus XLR 1
ZMYND10 607070 primary ciliary dyskinesia, 22 AR 1
ZNF423 604557 nephronophthisis 14; Joubert syndrome 19 AD, AR 10

A major treatment for Kallmann syndrome is hormone replacement therapy, based on the use of testosterone in males and estradiol in females. In addition, human chorionic gonadotropin (hCG) injections in males or progestin in females can be used in order to stimulate spermatogenesis or folliculogenesis. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization may be an option.

CENTOGENE offers sequencing and deletion/duplication analysis for the Kallmann syndrome and Hypogonadotropic hypogonadism panel (genes: ANOS1, CHD7, DUSP6, FEZF1, FGF17, FGF8, FGFR1, FLRT3, FSHB, GNRH1, GNRHR, HESX1, HS6ST1, IL17RD, KISS1, KISS1R, LHB, NSMF, PROK2, PROKR2, SEMA3A, SPRY4, TAC3, TACR3, WDR11). We also offer single gene tests for each gene included in the panel.


Differential diagnosis

The differential diagnosis of Kallmann syndrome related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Amenorrhea
  • Borjeson-Forssman-Lehmann syndrome
  • CHARGE syndrome
  • Constitutional growth delay
  • Erectile dysfunction
  • Follicle-stimulating hormone abnormalities
  • Infertility
  • Klinefelter syndrome
  • LEOPARD syndrome
  • Laurence-Moon-Biedl syndrome
  • Luteinizing hormone deficiency
  • Luteinizing hormone–releasing hormone deficiency
  • Martsolf syndrome
  • Prader-Willi syndrome
  • Rothmund-Thomson syndrome
  • Turner syndrome
  • Septooptic dysplasia.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Kallmann syndrome using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Kallmann syndrome panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Kallmann syndrome panel, we further recommend continuing the bioinformatics analysis of the data with whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.


Referral reasons

The following individuals are candidates for Kallmann syndrome gene testing:

  • Individuals with a family history of Kallmann syndrome and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling Kallmann syndrome
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of Kallmann syndrome related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with Kallmann syndrome should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Kallmann syndrome, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.