Novel homozygous variant in the TPO gene associated with congenital hypothyroidism and mild-intellectual disability

AbstractCongenital hypothyroidism (CH) is one of the most common hereditary disorders affecting neonates worldwide. CH is a multifactorial complex disorder and can be caused by either environmental factors or genetic factors. We studied one Pakistani family with segregating mutations in CH inherited in an autosomal recessive manner. Using whole-exome sequencing (WES), we found a novel homozygous missense variant (c.2315A>G; p.Tyr772Cys) in the thyroid peroxidase (TPO) gene. Different bioinformatics prediction tools and Sanger sequencing were performed to verify the identified variant. Our findings highlight the importance of this gene in causing CH and mild-intellectual disability (ID) in two affected brothers. WES is a convenient and useful tool for the clinical diagnosis of CH and other associated disorders.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

2021 ◽

pp. mcs.a006130

Author(s):

Ryan J Patrick ◽

Jill M Weimer ◽

Laura Davis-Keppen ◽

Megan L Landsverk

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Facial Features ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

European Journal of Human Genetics ◽

10.1038/s41431-019-0506-2 ◽

2019 ◽

Vol 28 (3) ◽

pp. 373-377 ◽

Cited By ~ 2

Author(s):

Sunitha Balaraju ◽

Ana Töpf ◽

Grace McMacken ◽

Veeramani Preethish Kumar ◽

Astrid Pechmann ◽

...

Keyword(s):

Intellectual Disability ◽

Haplotype Analysis ◽

Missense Variant ◽

Congenital Myasthenic Syndrome ◽

Single Family ◽

Mild Intellectual Disability ◽

Causative Gene ◽

Whole Exome ◽

Original Family ◽

Myasthenic Syndrome

Abstract Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.

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Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14

Scientific Reports ◽

10.1038/s41598-021-02599-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Stephen F. Pastore ◽

Tahir Muhammad ◽

Ricardo Harripaul ◽

Rebecca Lau ◽

Muhammad Tariq Masood Khan ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Ion Homeostasis ◽

Cerebellar Atrophy ◽

Chloride Ion ◽

Hek293 Cells ◽

Retinol Dehydrogenase ◽

Gene Encoding ◽

Whole Exome ◽

Transcription Data

AbstractIn a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.

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Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability

Genes ◽

10.3390/genes12101583 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1583

Author(s):

Tim Phetthong ◽

Arthaporn Khongkrapan ◽

Natini Jinawath ◽

Go-Hun Seo ◽

Duangrurdee Wattanasirichaigoon

Keyword(s):

Intellectual Disability ◽

Point Mutation ◽

Williams Syndrome ◽

Autosomal Recessive ◽

Compound Heterozygote ◽

Facial Dysmorphism ◽

Seizure Disorders ◽

Unique Event ◽

Whole Exome ◽

Mrna Analysis

The OTUD6B and ZMIZ1 genes were recently identified as causes of syndromic intellectual disability (ID) with shared phenotypes of facial dysmorphism, distal limb anomalies, and seizure disorders. OTUD6B -and ZMIZ1 -related ID are inherited in autosomal recessive and autosomal dominant patterns, respectively. We report a 5-year-old girl with developmental delay, facial phenotypes resembling Williams syndrome, and cardiac defects. The patient also had terminal broadening of the fingers and polydactyly. Cytogenomic microarray (CMA), whole exome sequencing (WES), and mRNA analysis were performed. The CMA showed a paternally inherited 0.118 Mb deletion of 8q21.3, chr8:92084087–92202189, with OTUD6B involved. The WES identified a hemizygous OTUD6B variant, c.873delA (p.Lus291AsnfsTer3). The mother was heterozygous for this allele. The WES also demonstrated a heterozygous ZMIZ1 variant, c.1491 + 2T > C, in the patient and her father. This ZMIZ1 variant yielded exon 14 skipping, as evidenced by mRNA study. We suggest that Williams syndrome-like phenotypes, namely, periorbital edema, hanging cheek, and long and smooth philtrum represent expanded phenotypes of OTUD6B -related ID. Our data expand the genotypic spectrum of OTUD6B - and ZMIZ1 -related disorders. This is the first reported case of a compound heterozygote featuring point mutation, chromosomal microdeletion of OTUD6B, and the unique event of OTUD6B, coupled with ZMIZ1 variants.

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Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

10.1101/092346 ◽

2016 ◽

Author(s):

Ricardo Harripaul ◽

Nasim Vasli ◽

Anna Mikhailov ◽

Muhammad Arshad Rafiq ◽

Kirti Mittal ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Autosomal Recessive ◽

De Novo ◽

Clinical Diagnostics ◽

High Yield ◽

Disease Genes ◽

Missense Mutations ◽

Loss Of Function ◽

Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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A novel missense variant in GPT2 causes non-syndromic autosomal recessive intellectual disability in a consanguineous Iranian family

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2020.103853 ◽

2020 ◽

Vol 63 (5) ◽

pp. 103853 ◽

Cited By ~ 3

Author(s):

Sima Binaafar ◽

Ehsan Razmara ◽

Nejat Mahdieh ◽

Hamidreza Sahebjame ◽

Ali Reza Tavasoli ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Iranian Family

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Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10

BMC Medical Genetics ◽

10.1186/s12881-019-0895-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Amjad Khan ◽

Rongrong Wang ◽

Shirui Han ◽

Muhammad Umair ◽

Safdar Abbas ◽

...

Keyword(s):

Muscular Dystrophy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Missense Variant ◽

Pathogenic Variant ◽

Limb Girdle Muscular Dystrophy ◽

Molecular Diagnostic ◽

Sequencing Analysis ◽

Whole Exome

Abstract Background Limb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible. Aim This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10. Methods DNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing. Results Whole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10. Conclusion We identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

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3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0412 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Radha Rama Devi Akella

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Genetic Diagnosis ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Postnatal Growth ◽

Compound Heterozygous ◽

Case Presentation ◽

Whole Exome ◽

Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

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Kabuki Syndrome: Identification of Two Novel Variants in KMT2Dand KDM6A

Molecular Syndromology ◽

10.1159/000513199 ◽

2021 ◽

pp. 1-9

Author(s):

Mehrnoosh Khodaeian ◽

Ehsan Jafarinia ◽

Fatemeh Bitarafan ◽

Shohreh Shafeii ◽

Navid Almadani ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Genetic Disorder ◽

Missense Variant ◽

Kabuki Syndrome ◽

Functional Studies ◽

Large Deletions ◽

Whole Exome ◽

Functionally Impaired ◽

And Function

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

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NOVEL HOMOZYGOUS VARIANT OF TBC1 DOMAIN FAMILY MEMBER 8 GENE IN FOUR LIBYAN SIBLINGS WITH AUTISTIC SPECTRUM DISORDER AND INTELLECTUAL DISABILITY WITHOUT EPILEPSY

Innovare Journal of Medical Sciences ◽

10.22159/ijms.2021.v9i6.41029 ◽

2021 ◽

pp. 1-4

Author(s):

ADEL ZEGLAM ◽

SUAD ALHMADI

Keyword(s):

Intellectual Disability ◽

Genetic Analysis ◽

Single Case ◽

Molecular Genetic ◽

Missense Variant ◽

Molecular Genetic Analysis ◽

Genetic Changes ◽

Single Case Report ◽

Whole Exome ◽

Number Of Genes

Objective: Recent progress in genetic analysis and investigations have enabled researchers to identify potential genetic changes that may play a role in ASD. The number of genes connected with autism is growing. Whole exome sequencing(WES) identified the homozygous TBC1D8 variant. Aim to report for the first time a TBC1D8 missense variant (c.1883G>A, p. (Arg628Gln) in 4 Libyan children (3 homozygous,1 heterozygous) with severe neurodevelopmental phenotypes ASD and intellectual disability ID . Based on the data of HGMD and ClinVar, variants in only a few autosomal recessive intellectual disability ARID genes seem to be reported frequently. Method: Molecular genetic analysis of (WES) was carried out on blood samples from these children. The outcome of the genetic investigations was interpreted within the context of clinical finding, family history, and suspected mode of inheritance. Results: The number of genes associated with autism is increasing. WES identified the TBC1D8 variant. According to the longest isoform (NM_001102426.1),the nomenclature of this variant is c.1883G>A, p. (Arg628Gln) in TBC1D8 which leads to an amino acid exchange. This variant has not previously reported or described in the literature (PubMed, HGMD). Conclusion: we have provided evidence for a connection between TBC1D8 variant and ASD and ID; however, this evidence should be considered preliminary in the context of a single case report and such findings need to be replicated to gain insight in order to determine if ASD and ID are a characteristic of this variant.

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