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. 2020 Mar 28;140(1):113–134. doi: 10.1007/s00439-020-02148-0

Table 4.

Variants identified by targeted NGS panel in 38 CHH probands

Patient ID Sex Clinical diagnosis Gene_name Inheritance Variant identified ACMG classification Minor allele frequency (MAF) Prediction (DANN) Gene Reference Variant Reference (HGMD ID, Ref)
HGVS cdna HGVS prot Zygosity Total Eu (non-Finnish)
Probands (n = 38)
 3 F KS, anosmia (primer amenorrhea) PROKR2 AD, contributes to oligogenicity NM_144773.3:c.518 T > G p.Leu173Arg Heterozygous Likely pathogenic 0.00229 0.00347 0.9976 Boehm et al. (2015) Dodé et al. (2006), Cole et al. (2008), Monnier et al. (2009), Abreu et al. (2010), Reynaud et al. (2012), Cassatella et al. (2018), Amato et al. (2019)
 5 M KS AMH AR (Malone et al. 2019) NM_000479.4:c.1556C > T p.Ala519Val Heterozygous VUS 0.00159 0.00252 0.9582 Malone et al. (2019)

Novel in IHH

(It was deteceted in a DSD case by Hughes et al. (2019))
JAG1 AD (Quaynor et al. 2016) NM_000214.3:c.3109G > A p.Asp1037Asn Heterozygous VUS 0.00000795 0.0000176 0.9918 Quaynor et al. (2016) Novel in IHH
 10 M KS, anosmia, pubertal delay FGFR1 AD, contributes to oligogenicity NM_001174067.1:c.417delCa p.Ser140ArgfsTer43 heterozygous Pathogenic Absent Absent na Boehm et al. (2015) Novel in IHH
IL17RD AD, AR or digenic dominant, contributes to oligogenicity NM_017563.5:c.1696C > T p.Pro566Ser Heterozygous VUS 0.0144 0.0214 0.9981 Boehm et al. (2015)

Novel in IHH

[Amato et al. (2019) found a pathogenic variant in the same codon: c.1697C > T; p.Pro566Leu]
 12 M PDE3A Digenic (Quaynor et al. 2016) NM_000921.4:c.293C > A p.Ala98Glu Heterozygous VUS 0.000431 0.000884 0.7627 Quaynor et al. (2016) Novel in IHH
 13 M KS ANOS1 XR, contributes to oligogenicity NM_000216.4:c.1700G > A p.Gly567Asp Hemizygous Likely pathogenic Absent Absent 0.9959 Boehm et al. (2015) Novel in IHH
 15 M KS, anosmia, parosmia GNRHR AR, contributes to oligogenicity NM_000406.2:c.416G > A p.Arg139His Heterozygous Likely pathogenic 0.000144 0.000168 0.9994 Boehm et al. (2015) Costa et al. (2001), Topaloglu et al. (2006), Beneduzzi et al. (2014)
 16 M KS GLI3 digenic (Quaynor et al. 2016) NM_000168.6:c.2179G > A p.Gly727Arg Heterozygous VUS 0.00527 0.00755 0.9994 Quaynor et al. (2016)

Novel in IHH

(Radhakrishna et al. 1999 detected in postaxial polydactyly type-A/B)
JAG1 AD (Quaynor et al. 2016) NM_000214.3:c.3320C > T p.Ser1107Phe Heterozygous VUS Absent Absent 0.9929 Quaynor et al. (2016) Novel in IHH
 17 M KS NOTCH1 AD? (Quaynor et al. 2016) NM_017617.5:c.4049G > T p.Arg1350Leu Heterozygous VUS 0.000604 0.00103 0.6583 Quaynor et al. (2016) Novel in IHH
 18 M nCHH, pubertal delay GLI3 digenic (Quaynor et al. 2016) NM_000168.6:c.2179G > A p.Gly727Arg Heterozygous VUS 0.00527 0.00755 0.9994 Quaynor et al. 2016

Novel in IHH

[Radhakrishna et al. (1999) detected in postaxial polydactyly type-A/B]
 20 M KS, anosmia, pubertal delay NOTCH1 AD? (Quaynor et al. 2016) NM_017617.5:c.3860G > A p.Arg1287His Heterozygous VUS 0.0000688 0.000191 0.9977 Quaynor et al. (2016) Novel in IHH
 23 M KS, anosmia FGFR1 AD, contributes to oligogenicity NM_001174067.1:c.1012delTa p.Tyr338MetfsTer5 Heterozygous Pathogenic – – na Boehm et al. (2015) Novel in IHH
 26 M nCHH, pubertal delay MASTL AD, di-, trigenic (Quaynor et al. 2016) NM_001172303.2:c.2120A > T p.His707Leu Heterozygous VUS 0.000004 0.000000 0.8767 Quaynor et al. (2016) Novel in IHH
TAC3 AR, contributes to oligogenicity NM_013251.4:c.248A>C p.His83Pro heterozygous VUS 0.000008 0.000009 0.977 Boehm et al. (2015)

Novel in IHH

[Cassatella et al. (2018) found a pathogenic variant in the same codon: c.248A>G; p.His83Arg]
 29 M nCHH GNRHR AR, contributes to oligogenicity NM_000406.2:c.350 T > G p.Leu117Arg Heterozygous Likely pathogenic absent absent 0.9971 Boehm et al. (2015)

HGMD ID: CM128135

Gürbüz et al. (2012),

Cassatella et al. (2018)
GNRHR AR, contributes to oligogenicity NM_000406.2:c.158A > T p.Asn53Ile Heterozygous VUS Absent Absent 0.9881 Boehm et al. (2015) Novel in IHH
 30 M nCHH NOTCH1 AD? (Quaynor et al. 2016) NM_017617.5:c.2734C > T p.Arg912Trp Heterozygous VUS 0.001710 0.002570 0.9989 Quaynor et al. (2016)

Novel in IHH

[Digilio et al. (2019) reported in association with cardiovascular anomalies]
PROKR2 AD, contributes to oligogenicity NM_144773.3:c.701G > A p.Gly234Asp Heterozygous VUS 0.000008 0.000018 0.9981 Boehm et al. (2015)

HGMD ID: CM1211225

Tommiska et al. (2013)
 31 M KS, hyposmia ANOS1 XR, contributes to oligogenicity NM_000216.4:c.1246dupAa p.Thr416AsnfsTer29 Hemizygous Pathogenic – – na Boehm et al. (2015) Novel in IHH
MASTL AD, di-, trigenic (Quaynor et al. 2016) NM_001172303.2:c.871C > T p.Leu291Phe Heterozygous VUS 0.000540 0.000940 0.9989 Quaynor et al. (2016) Novel in IHH
 32 M nCHH, pubertal delay TACR3 AR, contributes to oligogenicity NM_001059.2:c.1345G>T p.Ala449Ser Heterozygous VUS 0.000162 0.000305 0.9737 Boehm et al. (2015) Tusset et al (2012) reported in a case of CDGP
 33 M nCHH, pubertal delay AMHR2 AR (Malone et al. 2019) NM_020547.3:c.1484G > A p.Arg495Gln Heterozygous Likely pathogenica 0.000203 0.000009 0.9995 Malone et al. (2019) Novel in IHH
 35 M pubertal delay KISS1R AR NM_032551.5:c.581C > A p.Ala194Asp Heterozygous VUS 0.000352 0.000882 0.977 Boehm et al. (2015) Miraoui et al. (2013)
 36 M pubertal delay MASTL AD, di-, trigenic (Quaynor et al. 2016) NM_001172303.2:c.1505A > G p.Asp502Gly Heterozygous VUS Absent Absent 0.9219 Quaynor et al. (2016) Novel in IHH
 37 M pubertal delay SPRY4 AD NM_030964.3:c.626G > A p.Cys209Tyr Heterozygous VUSb 0.002170 0.003450 0.9971 Miraoui et al. (2013) HGMD ID: CM133832 Miraoui et al. (2013)
AMH AR (Malone et al. 2019) NM_000479.4:c.761G > C p.Arg254Pro Heterozygous VUSb 0.000015 0.000000 0.9626 Malone et al. (2019) Novel in IHH
 39 M KS FGFR1 AD, contributes to oligogenicity NM_001174067.1:c.367G>T p.Asp123Tyr Heterozygous VUS 0.000059 0.000000 0.9944 Boehm et al. (2015)

Novel in IHH

(It was reported in deafness variation database

https://deafnessvariationdatabase.org/)
GLI3 digenic (Quaynor et al. 2016) NM_000168.6:c.1163C > T p.Pro388Leu Heterozygous VUS Absent Absent 0.7657 Quaynor et al. (2016) Novel in IHH
 40 M KS FGFR1 AD, contributes to oligogenicity NM_001174067.1:c.550C > A p.Pro184Thr Heterozygous VUS Absent Absent 0.9974 Boehm et al. (2015) Novel in IHH

Gene references:

Boehm et al. (2015), Malone et al. (2019), Quaynor et al. (2016)

Variant references:

Dodé et al. (2006), Cole et al. (2008), Monnier et al. (2009), Abreu et al. (2010), Reynaud et al. (2012), Cassatella et al. (2018), Amato et al. (2019), Hughes et al. (2019), Costa et al. (2001), Topaloglu et al. (2006), Beneduzzi et al. (2014), Radhakrishna et al. (1999), Gürbüz et al. (2012), Digilio et al. (2019), Tommiska et al. (2013), Tusset et al. (2012), Miraoui et al. (2013)

aAfter family screening, we considered this variant not disease causing as the unaffected father carried the same variant in heterozygous form

bAfter family screening, we considered these variants not disease causing as the unaffected father carried both variants in heterozygous form