scholarly journals Novel GLIS3 mutations demonstrate an extended multisystem phenotype

2011 ◽  
Vol 164 (3) ◽  
pp. 437-443 ◽  
Author(s):  
P Dimitri ◽  
J T Warner ◽  
J A L Minton ◽  
A M Patch ◽  
S Ellard ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Gene Dosage ◽  
Molecular Genetic ◽  
Sensorineural Deafness ◽  
Neonatal Diabetes ◽  
Congenital Glaucoma ◽  
Facial Dysmorphism ◽  
Snp Analysis ◽  
Exocrine Insufficiency ◽  
First Case

IntroductionMutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with six affected cases from three families reported to date. Additional features, described previously, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and facial dysmorphism.SubjectsWe report two new cases from unrelated families with distinct novel homozygous partial GLIS3 deletions. Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism. These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations. Gene dosage analysis showed that the parents were carriers of a deletion encompassing exons 1–2 (case 1) or exons 1–4 (case 2) of the 11 exon gene. Genome-wide SNP analysis did not reveal a common ancestral GLIS3 haplotype in patient 2.ConclusionsOur results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date. We propose that mutations in GLIS3 lead to a wider clinical phenotype than previously recognised. We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype.

scholarly journals Case Report: Paternal Uniparental Isodisomy and Heterodisomy of Chromosome 16 With a Normal Phenotype

2021 ◽  
Vol 9 ◽  
Author(s):  
Xu Zhang ◽  
Li Liu ◽  
Yang Liu ◽  
Xin Pan
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Testing ◽  
Genetic Diseases ◽  
Molecular Genetic ◽  
Uniparental Disomy ◽  
Snp Analysis ◽  
Chromosome 16 ◽  
Pathogenic Variants ◽  
First Case ◽  
Whole Exome

Uniparental disomy (UPD) is a specific type of chromosomal variant that has been detected in both prenatal diagnosis and neonates with advances in molecular genetic testing technologies [mainly chromosome microarray analysis (CMA) technologies containing single-nucleotide polymorphism (SNP) probes]. In this case, we performed non-invasive prenatal genetic testing (NIPT) to screen fetuses for aneuploidy and detected the presence of aneuploidy chimerism and UPD by CMA, including SNP analysis and whole-exome sequencing, to detect pathogenic variants within the genome. The NIPT results suggested an increased number of fetal chromosome 16, and the CMA results indicated that it was the first case of holistic paternal UPD16 with isodisomy combined with heterodisomy, although no abnormal phenotype was seen in the newborn at postnatal follow-up. The homozygous region of the isodimer combined with the heterodimer is smaller than that of the complete isodimer, and it is less prone to recessive genetic diseases. A retrospective analysis of this case of paternally derived UPD16 was used to explore the uniparental diploid origin of chromosome 16 and to provide some reference for genetic counseling and prenatal diagnosis.

scholarly journals Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins

2021 ◽  
Vol 12 ◽  
Author(s):  
Shira London ◽  
Elisa De Franco ◽  
Ghadir Elias-Assad ◽  
Marie Noufi Barhoum ◽  
Clari Felszer ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Congenital Hypothyroidism ◽  
Nonsense Mutation ◽  
Stop Codon ◽  
Infusion Pump ◽  
Neonatal Diabetes ◽  
Neonatal Diabetes Mellitus ◽  
Congenital Glaucoma ◽  
Psychomotor Development ◽  
Cystic Kidney

BackgroundMutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in β-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys.CasesWe describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development. Sequence analysis of GLIS3 identified a novel homozygous nonsense mutation, c.2392C>T, p.Gln798Ter (p.Q798*), which results in an early stop codon. The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring. Fluctuating blood glucose and intermittent hypoglycemia were observed on follow-up.ConclusionsThis report highlights the importance of early molecular diagnosis for appropriate management of NDM. We describe a novel nonsense mutation of GLIS3 causing NDM, extend the phenotype, and discuss the challenges in clinical management. Our findings provide new areas for further investigation into the roles of GLIS3 in the pathophysiology of diabetes mellitus.

Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism

2020 ◽  
Vol 33 (6) ◽  
pp. 691-701 ◽  
Author(s):  
Tatsushi Tanaka ◽  
Kohei Aoyama ◽  
Atsushi Suzuki ◽  
Shinji Saitoh ◽  
Haruo Mizuno
Keyword(s):  
Congenital Hypothyroidism ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Japanese Patients ◽  
Thyroid Stimulating Hormone ◽  
Allelic Variant ◽  
Genetic Investigation ◽  
Pathogenic Variants ◽  
Recessive Genes ◽  
Molecular Genetic Diagnosis

AbstractObjectivesCongenital hypothyroidism (CH) is the most common congenital endocrine disorder. Recent advances in genetic testing have revealed its causative mutations in some CH patients. However, the underlying etiology remains unknown in most patients. This study aimed to perform clinical and genetic investigation in Japanese CH patients to uncover genotype-phenotype correlations.MethodsWe enrolled 136 Japanese patients with transient or permanent CH between April 2015 and March 2017, and performed next-generation sequencing of 19 genes implicated in CH.ResultsWe identified potentially pathogenic bi-allelic variants in DUOX2, TSHR, and TPO in 19, 5, and 1 patient, respectively (autosomal recessive), and a potentially pathogenic mono-allelic variant in NKX2-1 (autosomal dominant) in 1 patient. Molecular genetic diagnosis was highly suggested in 26 patients (19%) from 23 families. We also detected a potentially pathogenic mono-allelic variant in five recessive genes (DUOX2, TSHR, TG, DUOXA2, and TPO) in 31 unrelated patients (23%), although the pathogenicity of these variants remains inconclusive. Patients with bi-allelic DUOX2 variants showed a more severe clinical presentation in infancy than those with bi-allelic TSHR variants. However, this trend reversed beyond infancy. There were no statistical differences in initial thyroid stimulating hormone, free thyroxine, thyroglobulin, and levothyroxine dose as of March 2017 between patients with bi-allelic and mono-allelic DUOX2 variants.ConclusionsThe prevalence of potentially-pathogenic variants in Japanese CH patients was similar to that found by previous reports. Our study demonstrates a genotype-phenotype correlation in Japanese CH patients.

scholarly journals Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) Contiguous Gene Syndromes by Chromosome Engineering in Mice: Phenotypic Consequences of Gene Dosage Imbalance

2003 ◽  
Vol 23 (10) ◽  
pp. 3646-3655 ◽  
Author(s):  
Katherina Walz ◽  
Sandra Caratini-Rivera ◽  
Weimin Bi ◽  
Patricia Fonseca ◽  
Dena L. Mansouri ◽  
...  
Keyword(s):  
Gene Dosage ◽  
Molecular Genetic ◽  
Chromosome 17 ◽  
Craniofacial Abnormalities ◽  
Chromosome 11 ◽  
Chromosome Engineering ◽  
Mild Phenotype ◽  
Contiguous Gene ◽  
Genomic Interval ◽  
Dosage Imbalance

ABSTRACT Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).

scholarly journals MED13L-related intellectual disability due to paternal germinal mosaicism

2021 ◽  
pp. mcs.a006124
Author(s):  
Beata Bessenyei ◽  
Istvan Balogh ◽  
Attila Mokanszki ◽  
Aniko Ujfalusi ◽  
Rolph Pfundt ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Mediator Complex ◽  
Facial Dysmorphism ◽  
Facial Features ◽  
Speech Delay ◽  
Motor Delay ◽  
First Case ◽  
Intragenic Deletion ◽  
Germinal Mosaicism

The MED13L-related intellectual disability or MRFACD syndrome (Mental retardation and distinctive facial features with or without cardiac defects; MIM # 616789) is one of the most common form of syndromic intellectual disability with about a hundred cases reported so far. Affected individuals share overlapping features comprising intellectual disability, hypotonia, motor delay, remarkable speech delay, and a recognizable facial gestalt. De novo disruption of the MED13L gene by deletions, duplications or sequence variants has been identified deleterious. Siblings affected by intragenic deletion transmitted from a mosaic parent have been reported once in the literature. We now present the first case of paternal germinal mosaicism for a missense MED13L variant causing MRFACD syndrome in one of the father's children and be the likely cause of intellectual disability and facial dysmorphism in the other. As part of the Mediator complex, the MED proteins have an essential role in regulating transcription. 32 subunits of the Mediator complex genes have been linked to congenital malformations that are now acknowledged as transcriptomopathies. The MRFACD syndrome has been suggested to represent a recognizable phenotype.

Gene of the month: GLIS1-3

2020 ◽  
Vol 73 (9) ◽  
pp. 527-530
Author(s):  
Karen Pinto ◽  
Runjan Chetty
Keyword(s):  
Autosomal Recessive ◽  
Interstitial Fibrosis ◽  
Neonatal Diabetes ◽  
Diagnostic Value ◽  
Cystic Kidney Disease ◽  
Cystic Kidney ◽  
Facial Dysmorphism ◽  
Loss Of Function ◽  
Tubular Atrophy ◽  
Colon Cancers

The GLIS 1–3 genes belong to a family of transcription factors, the Krüppel-like zinc finger proteins. The GLIS proteins function primarily as activators of transcription (GLIS 1 and 3), while GLIS 2 functions as a repressor. Collectively, the GLIS proteins are involved in a variety of diseases in several organs ranging from Alzheimer’s disease, facial dysmorphism, neonatal diabetes mellitus, breast and colon cancers and leukaemia. In particular, loss-of-function mutations in GLIS2 are responsible for an autosomal recessive cystic kidney disease called nephronophthisis, which is characterised by tubular atrophy, interstitial fibrosis and corticomedullary cysts.Of diagnostic value in current practice are the presence of GLIS 3 and 1 fusions with PAX8 in almost 100% of hyalinising trabecular tumours of the thyroid gland. This enables its separation from papillary thyroid cancer.

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