Unique near-complete deletion of GLI2 in a patient with combined pituitary hormone deficiency and post-axial polydactyly

Elizabeth, Melitza; Verkerk, Annemieke J.M.H.; Hokken-Koelega, Anita; Verlouw, Joost A M; Argente, Jesús; Pfaeffle, Roland; Visser, Theo J.; Peeters, Robin P.; Graaff, Laura C. G. de

doi:10.1016/j.ghir.2019.10.002

Cited by 7 publications

(7 citation statements)

References 38 publications

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“…This suggests that other factors apart from the canonical HH pathway are likely to be involved in holoprosencephaly malformation associated with SHH mutations. GLI 2 mutations are mostly associated with mild midfacial abnormalities, hypopituitarism and polydactyly with genito urinary tract anomalies in some cases rather than patent holoprosencephaly, despite abnormal HH signalling [ 109 ], with holoprosencephaly reported in only a minority (about 2%) of patients [ 110 ], possibly due to deletion of genes adjacent to GLI2 [ 111 ]. This is unlike patients with SHH mutations who present with varying abnormalities in the holoprosencephaly spectrum.…”

Section: Short-rib Polydactyly Syndromesmentioning

confidence: 99%

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes

Loo

Pearen

Ramm

2021

IJMS

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The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. SHH mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.

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Section: Short-rib Polydactyly Syndromesmentioning

confidence: 99%

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes

Loo

Pearen

Ramm

2021

IJMS

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“…We analyzed the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants, including the three reported here, for common findings (Figure 2) (Babu et al, 2019; Bertolacini et al, 2012; Culler & Jones, 1984; Demiral et al, 2020; Elizabeth et al, 2020; Elward et al, 2020; Flemming et al, 2013; França et al, 2010; Kremer Hovinga et al, 2018; Martín‐Rivada et al, 2019; Rahimov et al, 2006; Roessler et al, 2003; Shirakawa et al, 2018; Solomon et al, 2012; Vishnopolska et al, 2021). Hypopituitarism affected 58% (33/57) of the individuals.…”

Section: Clinical Reportmentioning

confidence: 99%

“…The phenotypes of pathogenic GLI2 variants vary from isolated PAP or short stature, to the triad of Culler–Jones Syndrome (CJS), through to more severe phenotypes including structural brain abnormalities and facial malformations (Bertolacini et al, 2012). In particular, the relationship between GLI2 variants and hypopituitarism has been well established in a number of case reports and cohort studies (Arnhold et al, 2015; Babu et al, 2019; Bear et al, 2014; Cohen, 2012; Demiral et al, 2020; Elizabeth et al, 2020; Elward et al, 2020; Flemming et al, 2013; França et al, 2010, 2013; Gregory et al, 2015; Juanes et al, 2016; Kremer Hovinga et al, 2018; Martín‐Rivada et al, 2019; Roessler et al, 2003; Solomon et al, 2012; Vishnopolska et al, 2021). GLI2 variants have also been associated with HPE in the literature.…”

Section: Introductionmentioning

confidence: 98%

Truncating and zinc‐finger variants in GLI2 are associated with hypopituitarism

Corder

Berland

Førsvoll

et al. 2021

American J of Med Genetics Pt A

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Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low‐risk variants. Four Zn‐finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn‐finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2‐related phenotypic variability. The most prevalent phenotypic feature is post‐axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.

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“…In recent years, the application of next generation sequencing methodologies (NGS), including the screening of large gene panels in many patients simultaneously, and whole exome sequencing have revealed new variants of known CPHD genes and new genes associated with CPHD [8][9][10]. However, the etiology of approximately 85% of the cases still remains unknown [3].…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

Sertedaki

Tatsi

Vasilakis

et al. 2022

Cells

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Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism.

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Unique near-complete deletion of GLI2 in a patient with combined pituitary hormone deficiency and post-axial polydactyly

Cited by 7 publications

References 38 publications

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes

The Role of Sonic Hedgehog in Human Holoprosencephaly and Short-Rib Polydactyly Syndromes

Truncating and zinc‐finger variants in GLI2 are associated with hypopituitarism

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency

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