Whole‐exome sequencing identified first homozygous frameshift variant in the <i>COLEC10</i> gene in an Iranian patient causing 3MC syndrome type 3

Mohammadi, Pouria; Siavashani, Elham Salehi; Mohammadi, Mohammad Farid; Bahramy, Afshin; Almadani, Navid; Garshasbi, Masoud

doi:10.1002/mgg3.1834

Cited by 11 publications

(5 citation statements)

References 27 publications

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“…The WES raw data (FastQ file) was analyzed by bioinformatics tools based on similar studies (Mohammadi, Daneshmand, et al, 2021 ; Mohammadi, Heidari, et al, 2021 ; Mohammadi, Salehi Siavashani, et al, 2021 ). The FastQC was used to perform quality control (QC) of reads based on GC content and Phred value (Gaur & Chaturvedi, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families

Ashrafi

Dehnavi

Tavasoli

et al. 2023

Molec Gen & Gen Med

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Background Giant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease‐causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families. Methods Clinical and imaging data of patients were recorded and evaluated, retrospectively. Whole‐exome sequencing (WES) was undertaken in order to detect disease‐causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013–2020. Results Three patients from two unrelated families were included. Using WES, we identified a novel nonsense variant [NM_022041.3:c.1162del (p.Leu388Ter)], in a 7‐year‐old boy of family 1, and a likely pathogenic missense variant [NM_022041.3:c.370T>A (p.Phe124Ile)], in two affected siblings of the family 2. Clinical examination revealed typical features of GAN‐1 in all three patients, including walking difficulties, ataxic gait, kinky hair, sensory‐motor polyneuropathy, and nonspecific neuroimaging abnormalities. Review of 63 previously reported cases of GAN indicated unique kinky hair, gait problem, hyporeflexia/areflexia, and sensory impairment were the most commonly reported clinical features. Conclusions One homozygous nonsense variant and one homozygous missense variant in the GAN gene were discovered for the first time in two unrelated Iranian families that expand the mutation spectrum of GAN. Imaging findings are nonspecific, but the electrophysiological study in addition to history is helpful to achieve the diagnosis. The molecular test confirms the diagnosis.

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Section: Methodsmentioning

confidence: 99%

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families

Ashrafi

Dehnavi

Tavasoli

et al. 2023

Molec Gen & Gen Med

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“…Whole exome sequencing and bioinformatics analysis was preformed as described previously [ 7 ]. Called variants were filtered considering minor allele frequency (MAF) > 0.01 based on the Gnome Aggregation Database (gnomAD v3) Consortium, and Iranome population databases [ 8 , 9 ].…”

Section: Case Presentationmentioning

confidence: 99%

Novel homozygous frameshift variant in the ATCAY gene in an Iranian patient with Cayman cerebellar ataxia; expanding the neuroimaging and clinical features: a case report

Siavashani,

Ashrafi,

Ghabeli

et al. 2023

BMC Med Genomics

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Background Pathogenic variants in the ATCAY gene are associated with a rare autosomal recessive disorder called Cayman cerebellar ataxia. Affected individuals display psychomotor retardation, cerebellar dysfunction, nystagmus, intention tremor, ataxic gait and dysarthric in some cases. Case presentation Whole exome sequencing was performed for a 21-month-old girl suffering from developmental delay specifically in motor and language aspects, hypotonia, nystagmus, pes planus and strabismus. The detected variant in the patient was confirmed by family segregation analysis by Sanger sequencing in both of her parents. Previously three homozygous variants in the ATCAY gene (missense, splice site and frameshift deletion) have been reported in patients with Cayman cerebellar ataxia. Here we report the fourth homozygous variant and the second homozygous frameshift deletion in this gene to be associated with autosomal recessive Cayman cerebellar ataxia. Conclusion The identification of this novel homozygous frameshift deletion in the ATCAY gene expands our understanding of the genetic landscape underlying Cayman cerebellar ataxia. Furthermore, the occurrence of this variant in Iran, in addition to Pakistan, signifies the importance of considering genotypic and phenotypic factors beyond ethnicity when studying this disorder. These findings contribute to the ongoing efforts to unravel the molecular basis of Cayman cerebellar ataxia and improve diagnostic approaches and potential therapeutic interventions.

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“…Variable features were reported that included short stature, blepharoptosis and epicanthus inversus, cleft lip/palate, congenital heart and kidney malformations, and skeletal anomalies of the digits, including clinodactyly and polydactyly. In these five patients, five novel variants were identified, including both loss of function variants and missense variants (Migliorero et al, 2021; Mohammadi et al, 2021; Munye et al, 2017). Here we describe nine individuals, from five separate families, with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 (NM_006438.3) and variable features of 3MC syndrome.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotypic spectrum of COLEC10‐Related 3MC syndrome: A glimpse into COLEC10‐Related 3MC syndrome in the Ashkenazi Jewish population

Rabin

Hirsch²,

Chung

et al. 2022

American J of Med Genetics Pt A

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Bi-allelic variants in COLEC11 and MASP1 have been associated with 3MC syndrome, a clinical entity made of up four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. More recently, bi-allelic variants in COLEC10 have been described to be associated with 3MC syndrome. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration. We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%. Molecular protein modeling suggested that the p.Gly104Val substitution alters local conformation. The c.311G > T (p.Gly104Val) variant likely represents a founder variant, and homozygosity is associated with features of 3MC syndrome. 3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate.

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Whole‐exome sequencing identified first homozygous frameshift variant in the COLEC10 gene in an Iranian patient causing 3MC syndrome type 3

Cited by 11 publications

References 27 publications

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families

Novel homozygous frameshift variant in the ATCAY gene in an Iranian patient with Cayman cerebellar ataxia; expanding the neuroimaging and clinical features: a case report

Expanding the phenotypic spectrum of COLEC10‐Related 3MC syndrome: A glimpse into COLEC10‐Related 3MC syndrome in the Ashkenazi Jewish population

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