scholarly journals Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

2021 ◽  
Vol 9 ◽  
Author(s):  
Niaz Muhammad Khan ◽  
Basharat Hussain ◽  
Chenqing Zheng ◽  
Ayaz Khan ◽  
Muhammad Shareef Masoud ◽  
...  
Keyword(s):  
Rural Areas ◽  
Autosomal Recessive ◽  
Brain Size ◽  
Significant Proportion ◽  
Clinical Syndrome ◽  
High Rate ◽  
Pakistani Population ◽  
Whole Exome ◽  
Variant Filtering ◽  
Autosomal Recessive Primary Microcephaly

Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MCPH5-associated gene. The founder mutation p.Trp1326* was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244* and p.Arg1019* were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of ASPM and expanded the Pakistani MCPH cohort.

scholarly journals Whole exome sequencing identifies a novel homozygous frameshift mutation in the ASPM gene, which causes microcephaly 5, primary, autosomal recessive

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2163
Author(s):  
Desaraju Suresh Bhargav ◽  
N. Sreedevi ◽  
N. Swapna ◽  
Soumya Vivek ◽  
Srinivas Kovvali
Keyword(s):  
Exome Sequencing ◽  
Autosomal Recessive ◽  
Frameshift Mutation ◽  
Protein Gene ◽  
Single Gene ◽  
Primary Microcephaly ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
The Family ◽  
Autosomal Recessive Primary Microcephaly

Microcephaly is a genetically heterogeneous disorder and is one of the frequently notable conditions in paediatric neuropathology which exists either as a single entity or in association with other co-morbidities. More than a single gene is implicated in true microcephaly and the list is growing with the recent advancements in sequencing technologies. Using massive parallel sequencing, we identified a novel frame shift insertion in the abnormal spindle-like microcephaly-associated protein gene in a client with true autosomal recessive primary microcephaly.  Exome sequencing in the present case helped in identifying the true cause behind the disease, which helps in the premarital counselling for the sibling to avoid future recurrence of the disorder in the family.

scholarly journals The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

2020 ◽  
Vol 21 (5) ◽  
pp. 1691 ◽  
Author(s):  
Xiaokun Zhou ◽  
Yiqiang Zhi ◽  
Jurui Yu ◽  
Dan Xu
Keyword(s):  
Autosomal Recessive ◽  
Brain Size ◽  
Cell Types ◽  
Primary Microcephaly ◽  
Current Therapies ◽  
Yin And Yang ◽  
The Common ◽  
Underlying Mechanisms ◽  
Different Cell Types ◽  
Autosomal Recessive Primary Microcephaly

The stem cells of neurogenesis and carcinogenesis share many properties, including proliferative rate, an extensive replicative potential, the potential to generate different cell types of a given tissue, and an ability to independently migrate to a damaged area. This is also evidenced by the common molecular principles regulating key processes associated with cell division and apoptosis. Autosomal recessive primary microcephaly (MCPH) is a neurogenic mitotic disorder that is characterized by decreased brain size and mental retardation. Until now, a total of 25 genes have been identified that are known to be associated with MCPH. The inactivation (yin) of most MCPH genes leads to neurogenesis defects, while the upregulation (yang) of some MCPH genes is associated with different kinds of carcinogenesis. Here, we try to summarize the roles of MCPH genes in these two diseases and explore the underlying mechanisms, which will help us to explore new, attractive approaches to targeting tumor cells that are resistant to the current therapies.

scholarly journals Normal early development in siblings with novel compound heterozygous variants in ASPM

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Taro Moriwaki ◽  
Narutoshi Yamazaki ◽  
Tetsumin So ◽  
Motomichi Kosuga ◽  
Osamu Miyazaki ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Pathogenic Variant ◽  
Compound Heterozygous ◽  
Normal Intelligence ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
Critical Regions ◽  
Autosomal Recessive Primary Microcephaly ◽  
The Relationship

AbstractAutosomal recessive primary microcephaly 5 (MCPH5) is caused by pathogenic variants in ASPM. Using whole-exome sequencing, we diagnosed two siblings with MCPH5. A known pathogenic variant (NM_018136.4: c.9697C > T, p.(Arg3233*)) and a novel pathogenic variant (c.1402_1406del, p.(Asn468Serfs*2)) of ASPM were identified in affected siblings with normal intelligence. Their pathogenic variants were not located in the critical regions of ASPM, but the relationship between the genotypes and their normal intelligence was unclear.

scholarly journals Molecular and Cellular Basis of Autosomal Recessive Primary Microcephaly

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Marine Barbelanne ◽  
William Y. Tsang
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Autosomal Recessive ◽  
Brain Size ◽  
Neurodevelopmental Disorder ◽  
Primary Microcephaly ◽  
Cycle Progression ◽  
Early Brain Development ◽  
Cycle Regulation ◽  
Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare hereditary neurodevelopmental disorder characterized by a marked reduction in brain size and intellectual disability. MCPH is genetically heterogeneous and can exhibit additional clinical features that overlap with related disorders including Seckel syndrome, Meier-Gorlin syndrome, and microcephalic osteodysplastic dwarfism. In this review, we discuss the key proteins mutated in MCPH. To date, MCPH-causing mutations have been identified in twelve different genes, many of which encode proteins that are involved in cell cycle regulation or are present at the centrosome, an organelle crucial for mitotic spindle assembly and cell division. We highlight recent findings on MCPH proteins with regard to their role in cell cycle progression, centrosome function, and early brain development.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14

2019 ◽  
Vol 19 (9) ◽  
pp. 683-687 ◽  
Author(s):  
Tawfiq Froukh ◽  
Ammar Hawwari
Keyword(s):  
Strong Evidence ◽  
Autosomal Recessive ◽  
Eye Diseases ◽  
Initial Reaction ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Consanguineous Family ◽  
Truncated Protein ◽  
Threonine Residue ◽  
Whole Exome

Background: Keratoconus (KC) is usually bilateral, noninflammatory progressive corneal ectasia in which the cornea becomes progressively thin and conical. Despite the strong evidence of genetic contribution in KC, the etiology of KC is not understood in most cases. Methods: In this study, we used whole-exome sequencing to identify the genetic cause of KC in two sibs in a consanguineous family. The Homozygous frameshift variant NM_001253826.1:c.60delC;p.Leu21Cysfs*6 was identified in the gene Nacetylgalactosaminyltransferase 14 (GALNT14). The variant does not exist in all public databases neither in our internal exome database. Moreover, no database harbours homozygous loss of function variants in the candidate gene. Result: GALNT14 catalyses the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D- galactosamine residue to a serine or threonine residue on target proteins especially Mucins. Conclusion: As alterations of mucin’s glycosylation are linked to a number of eye diseases, we demonstrate in this study an association between the truncated protein GALNT14 and KC.

scholarly journals Identification of a novel homozygous loss-of-function mutation in FUCA1 gene causing severe fucosidosis: A case report

2021 ◽  
Vol 49 (4) ◽  
pp. 030006052110059
Author(s):  
Xinwen Zhang ◽  
Shaozhi Zhao ◽  
Hongwei Liu ◽  
Xiaoyan Wang ◽  
Xiaolei Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lysosomal Storage Disorder ◽  
Autosomal Recessive ◽  
Signs And Symptoms ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Exon 1

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.

scholarly journals Human Microcephaly Protein RTTN Is Required for Proper Mitotic Progression and Correct Spindle Position

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1441
Author(s):  
En-Ju Chou ◽  
Tang K. Tang
Keyword(s):  
Brain Size ◽  
Neurodevelopmental Disorder ◽  
Mitotic Progression ◽  
Centriole Duplication ◽  
Spindle Poles ◽  
Multipolar Spindles ◽  
Mitotic Abnormalities ◽  
Cortical Localization ◽  
Spindle Position ◽  
Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the role of RTTN in mitosis is not fully understood. Here, we show that RTTN is required for normal mitotic progression and correct spindle position. The depletion of RTTN induces the dispersion of the pericentriolar protein γ-tubulin and multiple mitotic abnormalities, including monopolar, abnormal bipolar, and multipolar spindles. Importantly, the loss of RTTN altered NuMA/p150Glued congression to the spindle poles, perturbed NuMA cortical localization, and reduced the number and the length of astral microtubules. Together, our results provide a new insight into how RTTN functions in mitosis.

scholarly journals NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Xu ◽  
Yong-Biao Zhang ◽  
Li-Jun Liang ◽  
Jia-Li Tian ◽  
Jin-Ming Lin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Sanger Sequencing ◽  
Conformational Stability ◽  
Sequencing Analysis ◽  
Large Pedigree ◽  
Whole Exome ◽  
Variant Filtering ◽  
Genetic Contributions

Abstract Background Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. Methods We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. Results After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. Conclusions NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

scholarly journals Combination of Novel c.3484G> T/p.Glu162Ter Variant in ABCB11 and c.208G> A/p.Asp70Asn Variant in ATP8B1 Are Associated with Severe Symptoms in Progressive Family Intrahepatic Cholestasis

2020 ◽  
Vol 09 (04) ◽  
pp. 285-288
Author(s):  
Mervan Bekdas ◽  
Guray Can ◽  
Recep Eroz ◽  
Selma Erdogan Duzcu
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Bile Secretion ◽  
Peripheral Blood Sample ◽  
Portal Fibrosis ◽  
Traditional Treatment ◽  
Pathogenic Variants ◽  
Chronic Cholestasis ◽  
Whole Exome

AbstractProgressive family intrahepatic cholestasis (PFIC) is an autosomal recessive disease that causes chronic cholestasis. It is associated with pathogenic variants in genes that encode proteins involved in bile secretion to canaliculus from hepatocytes. In this study, we present a 16-year-old boy who presented with severe pruritus and cholestatic jaundice. All possible infectious etiologies were negative. A liver biopsy was consistent with intrahepatic cholestasis and portal fibrosis. DNA was isolated from a peripheral blood sample, and whole exome sequencing was performed. A novel c.3484G > T/p.Glu162Ter variant in the ABCB11 gene and a c.208G> A/p.Asp70Asn variant in the ATP8B1 gene were detected. Despite traditional treatment, the patient's recurrent severe symptoms did not improve. The patient was referred for a liver transplantation. This novel c.3484G > T/p.Glu162Ter variant is associated with a severe and recurrent presentation, and the two compound variants could explain the severity of PFIC.

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