Table 2. Gene variants in 37 families associated with PSIS.
| Case | Gene | Variant | ZY | mutation | Predicted effect on protein | dbSNP | ACMG classification | MAF and population (GnomAD) | In-house controls (MAF) | MI | Associated phenotypes (OMIM) | PV | GV | PR |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | PROP1 | NM_006261:c.63delG:p.L21fs | het | frameshift | loss-of-function | rs780134343 | Pathogenic | 0.0000961; African | Absent | AR | Pituitary hormone deficiency, combined, 2 (262600) | 44 | ||
| IL17RD | NM_017563:c.1256T>C:p.I419T | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.644 | rs145388838 | Likely pathogenic | 0.0001; NFE | Absent | AR/AD | Hypogonadotropic hypogonadism 18 with or without anosmia (606807) | ||||
| SMARCA2 | NM_001289396:c.787T>A:p.S263T | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.029 | Novel | Likely pathogenic | NA | Absent | AD | Nicolaides-Baraitser syndrome (601358) | ||||
| 2 | GLI3 | NM_000168.5:c.4180C>T:p.R1394C | het | missense | SIFT, deleterious; PolyPhen2, benign; REVEL 0.091 | rs577664817 | Uncertain significance | 0.00036; South Asian | Absent | AD | Greig cephalopolysyndactyly syndrome (175700); Pallister-Hall syndrome (146510); Polydactyly, postaxial, types A1 and B (174200); Polydactyly, preaxial, type IV (174700); Hypothalamic hamartomas, somatic (241800) | 43 | ||
| IL17RD | NM_017563:c.794C>G:p.P265L | het | missense | SIFT, deleterious; PolyPhen2, possibly damaging; REVEL. 0.432 | rs759628358 | Likely pathogenic | 0.000158; South Asian | Absent | AR/AD | Hypogonadotropic hypogonadism 18 with or without anosmia (606807) | ||||
| 3 | SHH | NM_000193.3:c.52G>T:p.V18L | het | missense | SIFT, tolerated; PolyPhen2, unknown; REVEL 0.349 | rs148181557 | Uncertain significance | 0.000096; African | Absent | AD | Holoprosencephaly 3 (142945); Microphthalmia with coloboma 5 (611638); Schizencephaly (269160); Single median maxillary central incisor (147250) | 45 | ||
| CHD7 | NM_017780:c.6377A>T:p.D2126V | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.345 | rs1064794182 | Uncertain significance | NA | Absent | AD | CHARGE syndrome (214800); Hypogonadotropic hypogonadism 5 with or without anosmia (612370) | 43 | |||
| 4 | NBAS | NM_015909:c.1083+4C>T | hom | essential splice site | Loss-of-function | rs112852390 | Uncertain significance | 0.014; African | 0.0032 | AR | Infantile liver failure syndrome 2 (616483); Short stature, optic nerve atrophy, and Pelger-Huet anomaly (614800) | |||
| KIAA0556 | NM_015202:c.3346+8G>T | het | essential splice site | Loss-of-function | rs374277288 | Uncertain significance | 0.0007; African | 0.001 | AR | Joubert syndrome 26 (616784) | 46 | |||
| KIAA0556 | NM_015202:c.2180A>T:p.H727L | het | missense | SIFT, deleterious; PolyPhen2, benign; REVEL 0.047 | rs139943989 | Uncertain significance | 0.0011; African | Absent | AR | Joubert syndrome 26 (616784) | 46 | |||
| ROBO1 | NM_002941:c.1565G>A:p.R522Q | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.139 | rs138082446 | Likely pathogenic | 0.0061; African | Absent | AD | NA | 17 | |||
| 5 | CHD7 | NM_017780:c.6476C>A:p.S2159Y | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.202 | Novel | Uncertain significance | NA | Absent | AD | CHARGE syndrome (214800); Hypogonadotropic hypogonadism 5 with or without anosmia (612370) | 43 | ||
| FANCA | NM_001286167:c.3971C>T:p.P1324L | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.714; | rs182657062 | Pathogenic | 0.0001; NFE | Absent | AR | Fanconi anemia, complementation group A (227650) | ||||
| FANCA | NM_001286167:c.1193_1196del:p.V398fs | het | frameshift | Loss-of-function | Novel | Pathogenic | NA | Absent | AR | Fanconi anemia, complementation group A (227650) | ||||
| GLI3 | NM_000168:c.1346GG>A:p.R449Q | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.175 | rs745809543 | Uncertain significance | 0.000045; NFE | Absent | AD | Greig cephalopolysyndactyly syndrome (175700); Pallister-Hall syndrome (146510); Polydactyly, postaxial, types A1 and B (174200); Polydactyly, preaxial, type IV (174700); Hypothalamic hamartomas, somatic (241800) | 43 | |||
| SEMA3E | NM_012431:c.C1498T:p.R500W | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.488 | rs111300014 | Uncertain Signficance | 0.0001; EAS | Absent | AD | CHARGE syndrome (214800) | ||||
| SLX4 (FANCP) | NM_032444:c.C3143T:p.S1048F | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.174 | Novel | Uncertain Significance | NA | Absent | AR | Fanconi anemia, complementation group P (613951) | ||||
| 6 | NBAS | NM_015909:c.G6311A:p.R2104Q | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.204 | rs773412024 | Uncertain Significance | 0.000097; African | Absent | AR | Infantile liver failure syndrome 2 (616483); Short stature, optic nerve atrophy, and Pelger-Huet anomaly (614800) | |||
| NBAS | NM_015909:c.T1118C:p.L373P | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.211 | Novel | Uncertain Significance | NA | Absent | AR | Infantile liver failure syndrome 2 (616483); Short stature, optic nerve atrophy, and Pelger-Huet anomaly (614800) | ||||
| CFTR | NM_000492:exon11:c.1520_1522del:p.507_508del | hom | Deletion | NA | rs113993960 | Pathogenic | 0.0106; NFE | 0.0034 | AR | Cystic fibrosis (219700) | ||||
| 7 | ROBO1 | NM_002941:c.G3450T:p.Y1150X | het | nonsense | Loss-of-function | Novel | Pathogenic | NA | Absent | AD | NA | 17 | 17 | |
| 8* | ROBO1 | NM_002941:c.G719C:p.C240S | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.542 | Novel | Pathogenic | 0.0001076; African | Absent | AD | NA | 17 | 17 | |
| 9 | WDR11 | NM_018117:c.T109G:p.Y37D | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.347 | rs776728184 | Likely pathogenic | 0.00003; NFE | Absent | AD | Hypogonadotropic hypogonadism 14 with or without anosmia (614858) | 13 | ||
| PMM2 | NM_000303:c.254_255del:p.Q85fs | het | frameshift | Loss-of-function | Novel | Uncertain Significance | NA | Absent | AR | Congenital disorder of glycosylation, type Ia (212065) | ||||
| 10** | ROBO1 | NM_002941:c.2928_2929delG, p.A977Qfs | het | Frameshift | Loss-of-function | Novel | Pathogenic | NA | Absent | AD | NA | 17 | 17 | |
| 11 | DNMT1 | NM_001130823.3:c.A2858G:p.D953G | het | Missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.780 | Novel | Likely pathogenic | NA | Absent | AD | Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant (604121); Neuropathy, hereditary sensory, type IE (614116) | |||
| 12 | NSMF | NM_001130969.1:c.C53A:p.S18X | het | Nonsense | Loss-of-function | Novel | Likely pathogenic | NA | Absent | AD | Hypogonadotropic hypogonadism 9 with or without anosmia (614838) | |||
| 13 | ARID1B | NM_020732:c.A5015T:p.N1672I | het | Missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.610 | Novel | Uncertain significance | NA | Absent | AD | Coffin-Siris syndrome 1 (135900) | 47 | ||
| VPS13B | NM_017890:c.C4298G:p.S1433C | het | Missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.532 | Novel | Uncertain significance | NA | Absent | AR | Cohen syndrome (216550) | ||||
| 14 | LHX9 | NM_020204:c.T2C:p.M1T | het | Missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.603 | rs201066309 | Uncertain significance | 0.00008637; AMR | Absent | NA | NA | |||
| INPP5E | NM_019892:c.G907A:p.V303M | het | Missense | SIFT, deleterious; PolyPhen2, possibly damaging; REVEL 0.699 | rs746212325 | Pathogenic | 0.00003472; NFE | Absent | AR | Joubert syndrome 1 (213300); Mental retardation, truncal obesity, retinal dystrophy, and micropenis (610156) | 43 | 25 | ||
| 15 | BMP4 | NM_130851:c.C1001T:p.A334V | het | missense | SIFT, deleterious; PolyPhen2, possibly damaging; REVEL 0.905 | rs550409227 | Uncertain significance | 0.00001499; NFE | Absent | AD | Microphthalmia, syndromic 6 (607932); Orofacial cleft 11 (600625) | 43 | ||
| SLX4 (FANCP) | NM_032444:c.G248C:p.G83A | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.048 | rs771698977 | Uncertain significance | 0.00005994; NFE | Absent | AR | Fanconi anemia, complementation group P (613951) | ||||
| 16 | CDON | NM_001243597:c.A1343G:p.H448R | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.119 | rs1209875838 | Uncertain significance | NA | Absent | AD | Holoprosencephaly 11 (614226) | 16 | ||
| 17 | GLI2 | NM_005270:c.G2455A:p.V819M | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL - | Novel | Uncertain significance | NA | Absent | AD | Culler-Jones syndrome (615849); Holoprosencephaly 9 (610829) | 43 | ||
| PTCH1 | NM_000264:c.G3929A:p.G1310D | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.348 | Novel | Uncertain significance | NA | Absent | AD | Holoprosencephaly 7 (610828) | ||||
| WDR11 | NM_018117:c.G3571A:p.G1191S | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.692 | rs149486212 | Likely pathogenic | 0.0002; NFE | Absent | AD | Hypogonadotropic hypogonadism 14 with or without anosmia (614858) | 13 | |||
| 18 | CDON | NM_001243597:c.T2764C:p.E922X | het | nonsense | Loss-of-function | Novel | Pathogenic | NA | Absent | AD | Holoprosencephaly 11 (614226) | 16 | ||
| 19 | CHD7 | NM_017780:c.G7085A:p.S2362N | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.120 | rs139876661 | Uncertain significance | 0.0023; African | Absent | AD | CHARGE syndrome (214800); Hypogonadotropic hypogonadism 5 with or without anosmia (612370) | 43 | ||
| GLI2 | NM_005270:c.G598A:p.A200T | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.171 | rs111840592 | Uncertain significance | 0.0045; African | Absent | AD | Culler-Jones syndrome (615849); Holoprosencephaly 9 (610829) | 43 | |||
| 20 | FANCG | NM_032656:c.C748T:p.Q86X | het | nonsense | Loss-of-function | Novel | Likely pathogenic | NA | Absent | NA | Fanconi anemia, complementation group G (614082) | |||
| SLX4 (FANCP) | NM_032444.3:c.G4445A:p.C1482Y | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.024 | rs148856258 | Uncertain significance | 0.00032; African | Absent | AR | Fanconi anemia, complementation group P (613951) | ||||
| 21 | FANCD2 | NM_0033044:c.1277_1278+5del | het | essential splice site | Loss-of-function | Novel | Uncertain significance | NA | Absent | AR | Fanconi anemia, complementation group D2 (227646) | |||
| RAF1 | NM_002880:c.A1756T:p.A586S | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.372 | Novel | Uncertain significance | NA | Absent | AD | Cardiomyopathy, dilated, 1NN (615916); LEOPARD syndrome 2 (611554); Noonan syndrome 5 (611553) | ||||
| 22 | CCDC141 | NM_173648:c.A2183G:p.N728S | het | missense | SIFT, tolerated; PolyPhen2, possibly damaging; REVEL 0.044 | rs151185557 | Uncertain significance | 0.0001; NFE | Absent | AR | NA | 43 | ||
| 23 | TBX19 | NM_005149:c.603+6->GTGTTTGT | homo | essential splice site | Loss-of-function | Novel | Uncertain significance | NA | Absent | AR | Adrenocorticotropic hormone deficiency (201400) | |||
| 24 | PRMT7 | NM_019023:c.T1480C:p.W494R | het | missense | SIFT, deleterious; PolyPhen2, possibly damaging; REVEL 0.598 | rs751670999 | Pathogenic | 0.000086; AMR | Absent | AR | Short stature, brachydactyly, intellectual developmental disability, and seizures (617157) | 36 | ||
| NKX2-1 | NM_001079668:c.G67C:p.G23R | het | missense | SIFT, tolerated; PolyPhen2, probably damaging; REVEL 0.332 | rs773410433 | Likely pathogenic | 0.00003286; South Asian | Absent | AD | Choreoathetosis, hypothyroidism, and neonatal respiratory distress (610978) | 41 | |||
| SOX11 | NM_003108:c.C885G:p.D295E | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL NA | Novel | Uncertain significance | NA | Absent | AD | Mental retardation, autosomal dominant 27 (615866) | ||||
| 25 | TGIF1 | NM_170695:c.T25C:p.S9P | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.078 | rs148390122 | Uncertain significance | 0.0057; African | Absent | AD | Holoprosencephaly 4 (142946) | 45 | ||
| FANCC | NM_000136:c.G137A:p.R46K | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.062 | rs765058606 | Uncertain significance | 0.00001499; NFE | Absent | AR | Fanconi anemia, complementation group C (227645) | ||||
| 26 | FGFR3 | NM_001163213:c.875A>T: p.E292V | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.494 | Novel | Uncertain significance | NA | Absent | AD | Achondroplasia (100800); CATSHL syndrome (610474); Crouzon syndrome with acanthosis nigricans (612247); Hypochondroplasia (146000); LADD syndrome (149730); Muenke syndrome (602849); SADDAN (616482); Thanatophoric dysplasia, type I (187600); Thanatophoric dysplasia, type II (187601) | |||
| 27 | KIAA0556 | NM_015202:c.G4836C:p.E1612D | het | missense | SIFT, tolerated; PolyPhen2, possibly damaging; REVEL 0.086 | rs775146768 | Uncertain significance | 0.00008639; AMR | Absent | AR | Joubert syndrome 26 (616784) | 46 | ||
| CSPP1 | NM_024790:c.A1972G:p.R658G | het | missense | SIFT, deleterious; PolyPhen2, benign; REVEL 0.107 | rs199996939 | Uncertain significance | 0.001; AMR | Absent | AR | Joubert syndrome 21 (615636) | 25 | |||
| 28 | CHD7 | NM_017780:c.C1696G:p.P566A | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.088 | rs764518030 | Uncertain significance | 0.0001172; Latino | Absent | AD | CHARGE syndrome (214800); Hypogonadotropic hypogonadism 5 with or without anosmia (612370) | 43 | ||
| WT1 | NM_024426:c.C278G:p.A93G | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL NA | Novel | Pathogenic | NA | Absent | AD | Denys-Drash syndrome (194080); Frasier syndrome (136680); Meacham syndrome (608978); Mesothelioma, somatic 156240);Nephrotic syndrome, type 4 (256370); Wilms tumor, type 1 (194070) | ||||
| WT1 | NM_024426:c.C250T:p.P84S | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.045 | Novel | Pathogenic | NA | Absent | AD | Denys-Drash syndrome (194080); Frasier syndrome (136680); Meacham syndrome (608978); Mesothelioma, somatic 156240);Nephrotic syndrome, type 4 (256370); Wilms tumor, type 1 (194070) | ||||
| FANCE | NM_021922:c.G1379A:p.R460Q | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.056 | rs541746126 | Uncertain significance | 0.00009619; African | bsent | AR | Fanconi anemia, complementation group E (600901) | ||||
| 29 | DHCR7 | NM_001163817:c.355delC:p.H119fs | het | frameshift | Loss-of-function | rs747827699 | Pathogenicv | 0.0000155; NFE | Absent | AR | Smith-Lemli-Opitz syndrome (270400) | 43 | ||
| ZNF423 | NM_015069:c.T1144C:p.S382P | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.145 | rs142835239 | Uncertain significance | 0.0014; NFE | Absent | AR/AD | Joubert syndrome 19 (614844); Nephronophthisis 14 (614844) | ||||
| FSHR | NM_000145:c.G1451A:p.R484H | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.250 | rs763241241 | Likely pathogenic | 0.0001; EAS | Absent | AR/AD | Ovarian dysgenesis 1 (233300); Ovarian hyperstimulation syndrome (608115); Ovarian response to FSH stimulation (276400) | ||||
| 30 | FGFR3 | NM_001163213:c.A2120G:p.K707R | het | missense | SIFT, deleterious; PolyPhen2, possibly damaging; REVEL 0.622 | rs369813768 | Uncertain significance | 0.00001534; NFE | Absent | AD | Achondroplasia (100800); CATSHL syndrome (610474); Crouzon syndrome with acanthosis nigricans (612247); Hypochondroplasia (146000); LADD syndrome (149730); Muenke syndrome (602849); SADDAN (616482); Thanatophoric dysplasia, type I (187600); Thanatophoric dysplasia, type II (187601) | |||
| CHD7 | NM_017780:c.A2185G:p.K729E | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.422 | rs41272437 | Uncertain significance | 0.0013; AMR | Absent | AD | CHARGE syndrome (214800); Hypogonadotropic hypogonadism 5 with or without anosmia (612370) | 43 | |||
| FANCD2 | NM_001018115:c.G3290A:p.R1097Q | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.372 | rs755748094 | Uncertain significance | 0.00007493; NFE | Absent | AR | Fanconi anemia, complementation group D2 (227646) | ||||
| 31 | CEP120 | NM_153223:c.A2114G:p.Y705C | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.365 | rs373838092 | Uncertain significance | 0.00006083; SAS | Absent | AR | Joubert syndrome 31 (617761); Short-rib thoracic dysplasia 13 with or without polydactyly (616300) | |||
| 32 | GLI2 | NM_005270.4:c.G2159A:p.R720H | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.446 | rs149091975 | Uncertain significance | 0.001366; African | 0.002 | AD | Culler-Jones syndrome (615849); Holoprosencephaly 9 (610829) | 43 | ||
| GLI2 | NM_005270.4:c.A538C:p.M180L | het | missense | SIFT, deleterious; PolyPhen2, benign; REVEL 0.249 | rs565813552 | Uncertain significance | 0.0003388; Latino | Absent | AD | Culler-Jones syndrome (615849); Holoprosencephaly 9 (610829) | 43 | |||
| SLIT2 | NM_004787.3:c.T3095C:p.L1032S | het | missense | SIFT, tolerated; PolyPhen2, probably damaging; REVEL 0.742 | rs768269055 | Uncertain significance | 0.0001388; Other | Absent | NA | NA | ||||
| 33 | CC2D2A | NM_001080522:c.G2356A:p.E786K | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.266 | Novel | Uncertain significance | NA | Absent | AR | COACH syndrome (216360); Joubert syndrome 9 (612285); Meckel syndrome (612284) | 43 | ||
| WDR11 | NM_018117:c.199-9T>C | het | essential splice site | Loss-of-function | rs565141290 | Uncertain significance | 0.000045; NFE | Absent | AD | Hypogonadotropic hypogonadism 14 with or without anosmia (614858) | 13 | |||
| 34 | CCDC141 | NM_173648.3:c.C1402T:p.R468W | het | missense | SIFT, deleterious; PolyPhen2, possibly damaging; REVEL 0.075 | rs550015011 | Uncertain significance | 0.007; African | 0.0007 | AD | NA | 43 | ||
| KISS1R | NM_032551.5:c.G710C:p.R237P | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL | Novel | Likely pathogenic | NA | Absent | AR | Hypogonadotropic hypogonadism 8 with or without anosmia (614837) | ||||
| 35 | KIAA0556 | NM_015202:c.G1232T:p.G411V | het | missense | SIFT, tolerated; PolyPhen2, benign; REVEL 0.080 | rs201073350 | Uncertain significance | 0.0002; NFE | Absent | AR | Joubert syndrome 26 (616784) | 46 | ||
| 36 | GATA5 | NM_080473.4:c.C56G:p.S19W | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.732 | rs200383755 | Uncertain significance | 0.005443; NFE | 0.0014 | AR/AD | Congenital heart defects, multiple types, 5 (617912) | |||
| 37 | HESX1 | NM_003865.2:c.G445A:p.E149K | het | missense | SIFT, deleterious; PolyPhen2, probably damaging; REVEL 0.937 | rs104893742 | Pathogenic | 0.00005016; East Asian | Absent | AR/AD | Pituitary hormone deficiency, combined, 5 (182230) | 11 | 11 |
Abbreviations. ZY zygosity, MI reported mode of inheritance, PV variant previously associated with the PSIS (reference), GV gene variants previously associated with the PSIS (reference), PR, variant previously reported in association with a mendelian disorder (reference), NFE non-finnish European, AMR mixed American, SAS South Asian, AR autosomal recessive, AD autosomal dominant, het heterozygous, hom homozygous, N/A not available.