A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling

Valenza, F.; Cittaro, Davide; Stupka, Elia; Biancolini, Donatella; Patricelli, Maria Grazia; Bonanomi, Dario; Lazarević, Dejan

doi:10.1371/journal.pone.0210097

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…Distinct clinical phenotypes in subjects with identical heterozygous GLI2 mutations have previously been reported and suggested as evidence for incomplete penetrance and variable expressivity (3,9). The variable expression of the GLI2 gene mutations has been attributed to the combination of genetic, environmental and epigenetic factors or contribution of the other genes involved in the SHH pathway, which include SHH, ZIC2, SIX3, PTCH1, GLI3 and TGIF genes (5,9,10,11). is a congenital anomaly of the pituitary gland characterized by small or absent anterior pituitary lobe, interrupted or absent pituitary stalk, and ectopic posterior pituitary lobe (18).…”

Section: Discussionmentioning

confidence: 99%

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the <i>GLI2</i> Gene

Demiral¹,

Demirbilek²,

Ünal³

et al. 2020

Jcrpe

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A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

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Section: Discussionmentioning

confidence: 99%

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the <i>GLI2</i> Gene

Demiral¹,

Demirbilek²,

Ünal³

et al. 2020

Jcrpe

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“…Subsequently, the girl was sequenced and two pathogenic variants (Table 1), including a splicing variant in the NF1 gene (c.6705-1G>A) and a frameshift variant in the GLI2 gene (c.1189del p.Val397CysfsTer124) were identi ed. Variants in GLI2 have been shown to cause short stature, abnormal development of brain structures, hypopituitarism and facial dysmorphism in Culler-Jones syndrome (MIM:615849) (19). We suggested this patient's presentation represents a mixture of distinct phenotypes, i.e., Cafe-au-Lait spots for NF type 1 (NF1, MIM:162200) and short stature for Culler-Jones syndrome (MIM:615849).…”

Section: Casementioning

confidence: 95%

Epidemiology and Phenotypic Characteristics of Dual Molecular Diagnosis Cases in Skeletal Abnormality

Lian

Sun

Chen

et al. 2021

Preprint

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Background Skeletal abnormality is a heterogeneous group of disorders that affects the composition and structure of bone and cartilage. In our previous studies, we have revealed that a substantial proportion of cases with early-onset scoliosis could be explained by monogenic disorders such as Marfan syndrome and Ehlers-Danlos syndrome. More recently complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal abnormalities. To explore the molecular epidemiology and phenotypic characteristics of dual diagnosis in skeletal abnormalities, we described cases with dual molecular diagnosis from the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study.Results In total, 1108 patients with skeletal abnormality from the DISCO study underwent Exome Sequencing. We identified eight probands with dual molecular diagnosis, including three (0.7%) from individuals with early-onset scoliosis (EOS), three (0.5%) from individuals with short stature, and two (2%) from individuals with congenital hand/foot deformity (CHFA). Other skeletal abnormalities observed in these individuals included bone fracture and interphalangeal joint contracture. All the eight probands have dual diagnosis of two autosomal dominant (AD) diseases. A total of 16 variants in 12 genes were identified. A substantial rate (5 of 10) of the identified causal variants were of de novo origin. The frequently observed molecular diagnoses (observed in more than one patient) include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700). These patients with dual molecular diagnosis often present blended phenotypes of two diseases, which significantly complicate their diagnostic process. Conclusions This study revealed the molecular epidemiology and complex diagnostic odyssey of dual molecular diagnosis through analyzing the clinical traits of skeletal abnormalities in eight patients.

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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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A novel truncating variant of GLI2 associated with Culler-Jones syndrome impairs Hedgehog signalling

Cited by 12 publications

References 44 publications

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the <i>GLI2</i> Gene

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the <i>GLI2</i> Gene

Epidemiology and Phenotypic Characteristics of Dual Molecular Diagnosis Cases in Skeletal Abnormality

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

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