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Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b).

ABSTRACT: BACKGROUND:Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. The high rates of consanguineous marriages in Iran provide a desirable context to facilitate finding the homozygous pathogenic mutations. This study designates to evaluate the clinical and genetic characteristics of patients with GSD1b to assess the possible genotype-phenotype correlation. RESULTS:Autozygosity mapping was performed on nineteen GSD suspected families to suggest the causative loci. The mapping was done using two panels of short tandem repeat (STR) markers linked to the corresponding genes. The patients with autozygous haplotype block for the markers flanking the genes were selected for direct sequencing. Six patients showed autozygosity in the candidate markers for SLC37A4. Three causative variants were detected. The recurrent mutation of c.1042_1043delCT (p.Leu348Valfs*53) and a novel missense mutation of c.365G?>?A (p.G122E) in the homozygous state were identified in the SLC37A4. In silico analysis was performed to predict the pathogenicity of the variants. A novel whole SLC37A4 gene deletion using long-range PCR and sequencing was confirmed as well. Severe and moderate neutropenia was observed in patients with frameshift and missense variants, respectively. The sibling with the whole gene deletion has shown both severe neutropenia and leukopenia. CONCLUSIONS:The results showed that the hematological findings may have an appropriate correlation with the genotype findings. However, for a definite genotype-phenotype correlation, specifically for the clinical and biochemical phenotype, further studies with larger sample sizes are needed.

SUBMITTER: Eghbali M

PROVIDER: S-EPMC6995048 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b).

Eghbali Maryam M Abiri Maryam M Talebi Saeed S Noroozi Zahra Z Shakiba Marjan M Rostami Parastoo P Alimadadi Hosein H Najafi Mehri M Yazarlou Fatemeh F Rabbani Ali A Modarressi Mohammad Hossein MH

Orphanet journal of rare diseases 20200131 1

<h4>Background</h4>Glycogen storage disease (GSD) is a rare inborn error of the synthesis or degradation of glycogen metabolism. GSD1, the most common type of GSD, is categorized into GSD1a and GSD1b which caused by the deficiency of glucose-6-phosphatase (G6PC) and glucose-6-phosphate transporter (SLC37A4), respectively. The high rates of consanguineous marriages in Iran provide a desirable context to facilitate finding the homozygous pathogenic mutations. This study designates to evaluate the ...[more]

PMID: 32005221

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Project description:Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-? signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (?(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

Dataset Information

Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b).

Publications

Genotype-phenotype correlation and description of two novel mutations in Iranian patients with glycogen storage disease 1b (GSD1b).

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