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

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

Human Genome Variation ◽

10.1038/s41439-020-00129-3 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Amjad Khan ◽

Muhammad Umair ◽

Rania Abdulfattah Sharaf ◽

Muhammad Ismail Khan ◽

Amir Ullah ◽

...

Keyword(s):

Intellectual Disability ◽

Congenital Hypothyroidism ◽

Autosomal Recessive ◽

Missense Variant ◽

Thyroid Peroxidase ◽

Mild Intellectual Disability ◽

Complex Disorder ◽

Whole Exome ◽

Hereditary Disorders ◽

Autosomal Recessive Manner

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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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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Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2015.11.002 ◽

2015 ◽

Vol 97 (6) ◽

pp. 886-893 ◽

Cited By ~ 95

Author(s):

Kym M. Boycott ◽

Chandree L. Beaulieu ◽

Kristin D. Kernohan ◽

Ola H. Gebril ◽

Aziz Mhanni ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Cerebellar Atrophy ◽

Zinc Transporter ◽

Transporter Gene

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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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Advances in identification of genes involved in autosomal recessive intellectual disability: a brief review

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105821 ◽

2019 ◽

Vol 56 (9) ◽

pp. 567-573 ◽

Cited By ~ 3

Author(s):

Yaser Rafiq Mir ◽

Raja Amir Hassan Kuchay

Keyword(s):

Intellectual Disability ◽

Large Scale ◽

Autosomal Recessive ◽

Biological Processes ◽

Autozygosity Mapping ◽

Whole Exome ◽

Recessive Disorders ◽

And Control ◽

Very High ◽

Dominant Genes

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1%–3% of the general population. The number of ID-causing genes is high. Many X-linked genes have been implicated in ID. Autosomal dominant genes have recently been the focus of several large-scale studies. The total number of autosomal recessive ID (ARID) genes is estimated to be very high, and most are still unknown. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause ARID has lagged behind, predominantly due to non-availability of sizeable families. A commonly used approach to identify genetic loci for recessive disorders in consanguineous families is autozygosity mapping and whole-exome sequencing. Combination of these two approaches has recently led to identification of many genes involved in ID. These genes have diverse function and control various biological processes. In this review, we will present an update regarding genes that have been recently implicated in ID with focus on ARID.

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FIG4-Associated Yunis-Varon Syndrome: Identification of a Novel Missense Variant

Molecular Syndromology ◽

10.1159/000516971 ◽

2021 ◽

pp. 1-7

Author(s):

Muhammad Umair ◽

Turki M. Alkharfy ◽

Sajida Sajjad ◽

Majid Alfadhel

Keyword(s):

Skeletal Muscles ◽

Autosomal Recessive ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Cleidocranial Dysplasia ◽

Gene Encoding ◽

Phosphoinositide Phosphatase ◽

Whole Exome ◽

Poor Outcomes

Yunis-Varon syndrome (YVS; OMIM 216340) is a rare heterogeneous autosomal recessive disorder with easy recognition of characteristic severe neurological and skeletal abnormalities involving skeletal muscles and cartilages. This cleidocranial dysplasia is characterized by bone and tooth disorders; it also affects the cardiovascular system and tissues from ectoderm with very poor outcomes. Rarely, mutations of the FIG4 gene, encoding a 50-phosphoinositide phosphatase have been identified as the cause for YVS. We report a neonate born to a consanguineous couple with typical clinical manifestations of YVS. Using whole-exome sequencing, we identified a novel homozygous missense variant (c.968A>G; p.Gln323Arg) in the FIG4 gene. Thus, our study expands the molecular and genetic spectrum of FIG4-associated mutations. To our knowledge, this is the first reported case of YVS from the Saudi population.

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Exome Sequencing Identifies a Novel Sorting Nexin 14 Gene Mutation Causing Cerebellar Atrophy and Intellectual Disability

Case Reports in Genetics ◽

10.1155/2018/6737938 ◽

2018 ◽

Vol 2018 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Nadia Al-Hashmi ◽

Mohammed Mohammed ◽

Salim Al-Kathir ◽

Naeema Al-Yarubi ◽

Patrick Scott

Keyword(s):

Intellectual Disability ◽

Gene Mutation ◽

Autosomal Recessive ◽

Cerebellar Atrophy ◽

Facial Features ◽

Loss Of Function ◽

Sorting Nexin ◽

The Family ◽

Cerebellar Ataxias ◽

High Level

The autosomal recessive cerebellar ataxias (ARCA) affect both the central and the peripheral nervous systems. They are also characterized by a relatively high level of genetic heterogeneity with well over 40 genes already implicated. The present study aimed to identify the gene mutation responsible for a complex phenotype comprising cerebellar ataxia and intellectual disability segregating in an Omani consanguineous family. Homozygosity-guided exome data analysis identified a novel frameshift mutation (c.2319_2322del) within the sorting nexin 14 gene (SNX14), which predicts complete absence of the SNX14 encoded protein. Segregation within the family of the sequence variation is consistent with its pathogenic role. Importantly, loss-of-function mutations in SNX14 have recently been described as a cause of a clinically distinguishable recessive syndrome consisting of cerebellar atrophy, ataxia, coarsened facial features, and intellectual disability. This study expands the genetic diversity of ataxia genes in the Omani population and have important implications for the clinical and molecular diagnosis of this condition in affected individuals.

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The PTRHD1 Mutation in Intellectual Disability

Archives of Iranian Medicine ◽

10.34172/aim.2021.110 ◽

2021 ◽

Vol 24 (10) ◽

pp. 747-751

Author(s):

Sara Cheraghi ◽

Sahar Moghbelinejad ◽

Hossein Najmabadi ◽

Kimia Kahrizi ◽

Reza Najafipour

Keyword(s):

Intellectual Disability ◽

Sanger Sequencing ◽

Autosomal Recessive ◽

Autosomal Recessive Inheritance ◽

Recessive Inheritance ◽

Consanguineous Family ◽

Causative Variant ◽

Whole Exome ◽

The Family ◽

High Throughput Dna Sequencing

Background: Intellectual disability (ID) is a heterogonous disorder with complex etiology. The frequency of autosomal recessive inheritance defects was elevated in a consanguineous family. Methods: In this study, high-throughput DNA sequencing was performed in an Iranian consanguineous family with two affected individuals to find potential causative variants. Whole-exome sequencing was carried out on the proband and Sanger sequencing was implemented for validation of the likely causative variant in the family members. Results: A novel homozygous missense mutation (p.Arg122Trp) was detected in the PTRHD1 gene. Conclusion: PTRHD1 has been recently introduced as a candidate ID and Parkinsonism causing gene. Our findings are in agreement with the clinical spectrum of PTRHD1 mutations; however, our affected individuals suffer from ID manifestations.

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Homozygosity mapping of autosomal recessive intellectual disability loci in 11 consanguineous Pakistani families

Acta Neuropsychiatrica ◽

10.1017/neu.2014.37 ◽

2014 ◽

Vol 27 (1) ◽

pp. 38-47 ◽

Cited By ~ 2

Author(s):

Iltaf Ahmed ◽

Muhammad Arshad Rafiq ◽

John B. Vincent ◽

Attya Bhatti ◽

Muhammad Ayub ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Homozygosity Mapping ◽

Recessive Mutation ◽

Sequencing Analysis ◽

Causative Gene ◽

Whole Exome ◽

Next Generation Sequencing Analysis ◽

Number Variation ◽

Recessive Genes

BackgroundAutosomal recessive intellectual disability (ID) is genetically heterogeneous and most of the genes causing it remain undiscovered.ObjectiveWe have ascertained 11 consanguineous families multiplex for IDs in order to identify new loci for autosomal recessive genes for non-syndromic ID, or to aid pinpointing mutations in known causative gene/loci.MethodologyMicroarray genotyping (Affymatrix 250K) was performed to identify homozygosity-by-descent (HBD) in all affected families.ResultsAnalysis of genotypes revealed 45 potential HBD regions across the families, although these may be rationalised down to 39. Two families share an overlapping HBD region on 7q11.21. In one family, X-linkage also looks plausible, and a new ID gene near the centromere may be a likely cause. In one family, no HBD region was found, and thus we exclude autosomal recessive mutation as the likely cause in this family. Copy-number variation (CNV) was also performed and revealed no CNVs, homozygous or heterozygous, segregating with the phenotype.ConclusionThe homozygous loci identified in this study might harbour candidate genes for ID in these studied families. Therefore, we are proceeding with next-generation sequencing analysis of the families, using whole-exome approaches, and anticipate that this will identify the causative gene/mutation within the identified HBD regions for many of the families studied here.

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