A case series of a mother and two daughters with a <i>GLI2</i> gene deletion demonstrating variable expressivity and incomplete penetrance

Elward, Cameron J.; Berg, Janet; Oberlin, John M.; Rohena, Luis

doi:10.1002/ccr3.3085

Cited by 6 publications

(6 citation statements)

References 10 publications

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“…Table 3 summarizes all 67 pathogenic CNVs published so far, found in 83 patients with CH, including the present study 5,13,14,16–65 . Forty‐five patients had their PP characterized by sellar MRI, 35 (78%) had EPP, two had absent PP and eight had normal PP.…”

Section: Resultsmentioning

confidence: 91%

Copy number variation in pituitary stalk interruption syndrome: A large case series of sporadic non‐syndromic patients and literature review

Correa‐Silva

Kunii

Mitne‐Neto

et al. 2022

J Neuroendocrinology

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Abnormal hypothalamic/posterior pituitary development appears to be a major determinant of pituitary stalk interruption syndrome (PSIS). The observation of familial cases and associated congenital abnormalities suggests a genetic basis. Single‐gene mutations explain less than 5% of the cases, and whole exome sequencing has shown heterogeneous results. The present study aimed to assess copy number variation (CNV) using array‐based comparative genomic hybridization (aCGH) in patients with non‐syndromic PSIS and comprehensively review data from the literature on CNV analysis in congenital hypopituitarism (CH) patients. Twenty‐one patients with sporadic CH from our outpatient clinics presented with ectopic posterior pituitary (EPP) and no central nervous system abnormalities on magnetic resonance image (MRI) or any other malformations on physical examination at presentation were enrolled in the study. aCGH using a whole‐genome customized 400K oligonucleotide platform was performed in our patients. For the literature review, we searched for case reports of patients with CH and CNV detected by either karyotype or aCGH reported in PubMed up to November 2021. Thirty‐five distinct rare CNVs were observed in 18 patients (86%) and two of them (6%) were classified as pathogenic: one deletion of 1.8 Mb in chromosome 17 (17q12) and one deletion of 15 Mb in chromosome 18 (18p11.32p11.21), each one in a distinct patient. In the literature review, 67 pathogenic CNVs were published in 83 patients with CH, including the present study. Most of these patients had EPP (78% out of the 45 evaluated by sellar MRI) and were syndromic (70%). The most frequently affected chromosomes were X, 18, 20 and 1. Our study has found that CNV can be a mechanism of genetic abnormality in non‐syndromic patients with CH and EPP. In future studies, one or more genes in those CNVs, both pathogenic and variant of uncertain significance, may be considered as good candidate genes.

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Section: Resultsmentioning

confidence: 91%

Copy number variation in pituitary stalk interruption syndrome: A large case series of sporadic non‐syndromic patients and literature review

Correa‐Silva

Kunii

Mitne‐Neto

et al. 2022

J Neuroendocrinology

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“…GLI2 was also deleted in Previous case 1, who had normal anterior pituitary gland function and no craniofacial anomalies but had clinodactyly and short stature. Genomic deletions encompassing GLI2 have been reported in nine patients ( 26 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ), and their typical phenotypes were short stature, polydactyly and intellectual disability. Anterior pituitary gland functions were evaluated in five patients: one had panhypopituitarism, but the others had normal anterior pituitary gland function although they had short stature.…”

Section: Discussionmentioning

confidence: 99%

A case of syndromic congenital hypothyroidism with a 15.2 Mb interstitial deletion on 2q12.3q14.2 involving <i>PAX8</i>

Iwahashi-Odano

Kitamura

Narumi

2023

Clin Pediatr Endocrinol

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“…GLI2 , SHH , and PTCH1 represent key hedgehog pathway members, which are critical for craniofacial patterning, and variations in these genes have been associated with holoprosencephaly with CL/P ( Roessler et al, 1996 ; Ribeiro et al, 2006 ). The GLI2 gene has been linked to Culler-Jones syndrome and Holoprosencephaly 9 (HPE9), and studies have reported that patients with pathogenic variants of the GLI2 gene demonstrate an autosomal dominant inheritance pattern, variable expressivity and incomplete penetrance ( Elward et al, 2020 ). Bertolacini et al reported the identification of a heterozygous 2-bp deletion (864delCC) in the GLI2 gene in a Brazilian family exhibiting variable manifestations of HPE9 ( Bertolacini et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing improves genetic diagnosis of congenital orofacial clefts

Yan,

Fu,

et al. 2023

Front. Genet.

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Objective: This retrospective study aims to evaluate the utility of exome sequencing (ES) in identifying genetic causes of congenital orofacial clefts (OFCs) in fetuses with or without other structural abnormalities, and to further explore congenital OFCs genetic causes.Methods: The study enrolled 107 singleton pregnancies diagnosed with fetal OFCs between January 2016 and May 2022, and categorized them into two groups: isolated cleft lip and/or palate (CL/CP) and syndromic CL/CP. Cases with positive karyotyping and chromosomal microarray analysis results were excluded. Whole-exome sequencing was performed on eligible fetuses and their parents. Monogenic variants identified by ES and perinatal outcomes were recorded and evaluated during postnatal follow-up.Results: Clinically significant variants were identified in 11.2% (12/107) of fetuses, with no significant difference in detection rate between the isolated CL/CP group and the syndromic CL/CP group (8/83, 9.6% vs. 4/24, 16.7%, p = 0.553). Additionally, sixteen (16/107, 15.0%) fetuses had variants of uncertain significance. We identified 12 clinically significant variations that correlated with clinical phenotypes in 11 genes from 12 fetuses, with CHD7 being the most frequently implicated gene (n = 2). Furthermore, we observed a significant difference in termination rates and survival rates between the isolated CL/CP and syndromic CL/CP groups (41.0% vs. 70.8% and 56.6% vs. 20.8%, p < 0.05 for both).Conclusion: Based on our findings, it is clear that ES provides a significant increase in diagnostic yield for the molecular diagnosis of congenital OFCs, thereby substantially improving the existing prenatal diagnostic capabilities. This study also sheds light on seven novel pathogenic variants, broadening our understanding of the genetic underpinnings of OFCs and expanding the disease spectrums of relevant genes.

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A case series of a mother and two daughters with a GLI2 gene deletion demonstrating variable expressivity and incomplete penetrance

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 6 publications

References 10 publications

Copy number variation in pituitary stalk interruption syndrome: A large case series of sporadic non‐syndromic patients and literature review

Copy number variation in pituitary stalk interruption syndrome: A large case series of sporadic non‐syndromic patients and literature review

A case of syndromic congenital hypothyroidism with a 15.2 Mb interstitial deletion on 2q12.3q14.2 involving <i>PAX8</i>

Exome sequencing improves genetic diagnosis of congenital orofacial clefts

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