A <scp><i>GLI3</i></scp> variant leading to polydactyly in heterozygotes and Pallister‐Hall‐like syndrome in a homozygote

Kariminejad, Ariana; Ghaderi‐Sohi, Siavash; Keshavarz, Elham; Hashemi, Seyed Abolghasem; Parsimehr, Elham; Szenker‐Ravi, Emmanuelle; Khatoo, Muznah; Zonooz, Mehrshid Faraji; Reversade, Bruno; Najmabadi, Hossein; Hennekam, Raoul C. M.

doi:10.1111/cge.13730

Cited by 6 publications

(5 citation statements)

References 16 publications

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“… Hom , homozygous, Compound het , compound heterozygous. a These cases have been previously published elsewhere 20 , 21 . b These individuals were reportedly healthy but had not undergone post-test clinical evaluation.…”

Section: Resultsmentioning

confidence: 99%

“…The clinical presentations in the majority of cases in this series were either similar to or more severe than the established dominant disorder. For example, in three separate cases with variants in TBX4 , GLI3 (both published elsewhere 20 , 21 ), and BICC1 genes, a severe embryonic condition was observed in the homozygous fetuses, while the heterozygous parents were either mildly affected or unaffected. Other remarkable examples include recessive forms of DCTN1 -related neurodegenerative disorder, KCNC3 -related spinocerebellar ataxia, HARS1 -related Charcot-Marie-Tooth disease 22 , and MITF -related hearing loss 23 .…”

Section: Resultsmentioning

confidence: 99%

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Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population

Abolhassani,

Fattahi,

Beheshtian

et al. 2024

npj Genom. Med.

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Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype–phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population

Abolhassani,

Fattahi,

Beheshtian

et al. 2024

npj Genom. Med.

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“…Recently, a fetus carrying a homozygous truncating variant in the GLI3 gene has been reported (Kariminejad et al, 2020). Both parents were heterozygous for the variant and presented with an isolated form of postaxial polydactyly and syndactyly.…”

Section: Discussionmentioning

confidence: 99%

Homozygous GLI3 variants observed in three unrelated patients presenting with syndromic polydactyly

Mouatani

Winckel

Zaafrane-Khachnaoui

et al. 2021

American J of Med Genetics Pt A

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Polydactyly is a hallmark of GLI3 pathogenic variants, with Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome being the two main associated clinical presentations. Homozygous GLI3 variants are rare instances in the literature, and mendelian dominance is the accepted framework for GLI3-related diseases. Herein, we report three unrelated probands, presenting with polydactyly, and homozygous variants in the GLI3 gene. First, a 10-year-old girl, whose parents were first-degree cousins, presented with bilateral postaxial polydactyly of the hands, developmental delay and multiple malformations. Second, a male newborn, whose parents were first-degree cousins, presented with isolated bilateral postaxial polysyndactyly of the hands and the feet. Third, an adult male, whose parents were first-degree cousins, had bilateral mesoaxial polydactyly of the hands, with severe intellectual disability and multiple malformations. All three probands carried homozygous GLI3 variants. Strikingly, the parents also carried the child's variant, in the heterozygous state, without any clinical sign of GLI3 disease. Given the clinical presentation of our patients, the rarity and predicted high pathogenicity of the variants observed, and the absence of other pathogenic variants, we suggest that these GLI3 homozygous variants are causal. Moreover, the parents were heterozygous for the observed variants, but were clinically unremarkable, suggesting that these variants are hypomorphic alleles.

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“…No Sufficient Evidence of Pathogenicity, but Variation With Pathogenicity Cannot Be Excluded GLI3 gene mutation was reported to be associated with Pallister-Hall syndrome (pHS; MIM 146510) (20), which was characterized by polydactyly, micropenis with undescended or hydroxyplastic testes in males, and urinary dysplasia. BCOR gene mutation is related to oculofaciocardiodental (OFCD) syndrome (OMIM 300166) (21), with clinical manifestations of microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities, as well as mild developmental delay, delayed motor development, and short stature.…”

Section: G6pd Gene Mutation: Likely Pathogenicmentioning

confidence: 99%

Case Report: Identification of Polygenic Mutations by Exome Sequencing

Liu¹,

Zheng²,

Zhu

2021

Front. Pediatr.

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The discovery of rare genetic variation through different gene sequencing methods is a very challenging subject in the field of human genetics. A case of a 1-year-old boy with metabolic acidosis and hypokalemia, a small penis, growth retardation, and G-6PD deficiency was reported. Since the clinical symptoms are complex and seem uncorrelated, the authors hypothesized that the child had chromosome or gene problems, and exome sequencing (ES) was applied to samples from him and his parents. Three main locus mutations in three genes were found in the proband, including SLC4A1, FGFR1, and G6PD genes. A missense mutation (c.1766G>T, p.R589 L) was found in exon 14 of SLC4A1 gene, which was a de novo mutation. Another missense mutation (c.1028 A>G, p.H343R) was found in exon 9 of FGFR1 gene, which was also a de novo mutation. These findings further demonstrate the utility of ES in the diagnosis of rare diseases.

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A GLI3 variant leading to polydactyly in heterozygotes and Pallister‐Hall‐like syndrome in a homozygote

Cited by 6 publications

References 16 publications

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population

Homozygous GLI3 variants observed in three unrelated patients presenting with syndromic polydactyly

Case Report: Identification of Polygenic Mutations by Exome Sequencing

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