scholarly journals Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Neil V Morgan ◽  
Bryndis Yngvadottir ◽  
Mary O’Driscoll ◽  
Graeme R Clark ◽  
Diana Walsh ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Neurological Disease ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Disease Status ◽  
Missense Variant ◽  
Spastic Cerebral Palsy ◽  
Single Family ◽  
Loss Of Function ◽  
Candidate Mutation

Abstract A subset of individuals diagnosed with cerebral palsy will have an underlying genetic diagnosis. Previously, a missense variant in GAD1 was described as a candidate mutation in a single family diagnosed with autosomal recessive spastic cerebral palsy-1 (CPSQ1; OMIM 603513). Following the ascertainment of a further branch of the CPSQ1 kindred, we found that the previously reported GAD1 variant did not segregate with the neurological disease phenotype in the recently ascertained branch of the kindred. Following genetic linkage studies to map autozygous regions and whole-exome sequencing, a missense variant (c.527 T > C; p. Leu176Pro, rs773333490) in the HPDL gene was detected and found to segregate with disease status in both branches of the kindred. HPDL encodes a 371-amino acid protein (4-Hydroxyphenylpyruvate Dioxygenase Like) that localizes to mitochondria but whose function is uncertain. Recently, biallelic loss of function variants and missense substitution-causing variants in HPDL were reported to cause a childhood onset progressive spastic movement disorder with a variable presentation. These findings suggest that HPDL-related neurological disease may mimic spastic cerebral palsy and that GAD1 should not be included in diagnostic gene panels for inherited cerebral palsy.

scholarly journals An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retardation

2006 ◽  
Vol 140A (14) ◽  
pp. 1504-1510 ◽  
Author(s):  
Anna Rajab ◽  
Seung-Yun Yoo ◽  
Aiman Abdulgalil ◽  
Salem Kathiri ◽  
Riaz Ahmed ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Mental Retardation ◽  
Autosomal Recessive ◽  
Spastic Cerebral Palsy ◽  
Autosomal Recessive Form ◽  
Recessive Form

scholarly journals A Gene for Autosomal Recessive Symmetrical Spastic Cerebral Palsy Maps to Chromosome 2q24-25

1999 ◽  
Vol 64 (2) ◽  
pp. 526-532 ◽  
Author(s):  
D.P. McHale ◽  
S. Mitchell ◽  
S. Bundey ◽  
L. Moynihan ◽  
D.A. Campbell ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Autosomal Recessive ◽  
Spastic Cerebral Palsy

scholarly journals Cohesin complex-associated holoprosencephaly

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2631-2643 ◽  
Author(s):  
Paul Kruszka ◽  
Seth I Berger ◽  
Valentina Casa ◽  
Mike R Dekker ◽  
Jenna Gaesser ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Cohesin Complex ◽  
Loss Of Function ◽  
Aberrant Expression ◽  
Human Neural Stem Cells ◽  
Forebrain Development ◽  
Important Regulator

Abstract Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

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

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.

scholarly journals A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

2019 ◽  
Author(s):  
Kejia Zhang ◽  
Jenna M Lentini ◽  
Christopher T Prevost ◽  
Mais O Hashem ◽  
Fowzan S Alkuraya ◽  
...  
Keyword(s):  
Protein Folding ◽  
Intellectual Disability ◽  
Human Population ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Trna Modification ◽  
Loss Of Function ◽  
Severe Deficiency ◽  
Trna Methyltransferase ◽  
The Impact

AbstractThe human TRMT1 gene encodes a tRNA methyltransferase enzyme responsible for the formation of the dimethylguanosine (m2,2G) modification in cytoplasmic and mitochondrial tRNAs. Frameshift mutations in the TRMT1 gene have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Moreover, the impact of ID-associated TRMT1 mutations on m2,2G levels in ID-affected patients is unknown. Here, we describe a homozygous missense variant in TRMT1 in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes a conserved arginine residue to a cysteine (R323C) within the methyltransferase domain of TRMT1 and is expected to perturb protein folding. Patient cells expressing the TRMT1-R323C variant exhibit a severe deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss-of-function. Notably, the TRMT1 R323C mutant retains the ability to bind tRNA but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that severely perturbs tRNA modification activity, and provide the first demonstration that m2,2G modifications are disrupted in patients with TRMT1-associated ID disorders.

scholarly journals Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

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.

scholarly journals Genetic study of a family with affected members with Waardenburg syndrome type 4 without Hirschsprung disease

2020 ◽  
Vol 18 (2) ◽  
pp. 93-100
Author(s):  
Mitra Sabetghadam Moghadam ◽  
◽  
Sima Rayat ◽  
Saeid Morovvati ◽  
◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Direct Sequencing ◽  
Genetic Diagnosis ◽  
Sensorineural Deafness ◽  
Hirschsprung Disease ◽  
General Characteristic ◽  
Pathogenic Mutation ◽  
Recessive Trait ◽  
Waardenburg Syndrome ◽  
Single Family

Introduction. Waardenburg syndrome (WS) is an autosomally inherited disorder with the most common state compounding pigmentary abnormality and sensorineural deafness. The rarest type of the disease is WS4 with the general characteristic discriminated from other types by the attendance of Hirschsprung disease (HD). Among the several genes, one of the causative genes in WS4 is endothelin 3 (EDN3) with both autosomal recessive and dominant inheritance. Aim. The intention of the present study is to report a pathogenic mutation as the genetic cause of WS in an Iranian family with four patients without any segregation criteria for the type of the disease. Material and methods. In order to detect of causing gene or genes related to the disease, Whole exome sequencing (WES) technique in proband’s sample was done. To confirm the detected mutation in proband and some family members with or without the disease direct sequencing of END3 gene was performed using Sanger method. Results. Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. WES analysis suggested a gene (EDN3) related to WS type 4B. DNA sequencing confirmed a pathogenic missense mutation c.293C>T, p.T98M in EDN3 gene in all of the four patients. Conclusion. Determination of WS can usually be missed owing to the lack of some attributes in every sufferer and also conventional clinical variance, in spite of several affected members in a single family. So, Genetic counseling is pivotal for families with multiple members influenced. We detected c.293C>T, p.T98K mutation in EDN3 gene as a pathogenic variant which has been known as a likely pathogenic state in the American College of Medical Genetics and Genomics (ACMG) guidelines, despite one prior report. It will be helpful in genetic diagnosis of affected persons and increases the mutation spectrum of EDN3 gene.

scholarly journals Variants in the PNPLA1 Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance

2021 ◽  
pp. 1-11
Author(s):  
Farooq Ahmad ◽  
Ishtiaq Ahmed ◽  
Qamre Alam ◽  
Tanveer Ahmad ◽  
Ammara Khan ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Autosomal Recessive ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Sequence Variant ◽  
Phenotype Correlation ◽  
Congenital Ichthyosis ◽  
Whole Exome ◽  
Autosomal Recessive Congenital Ichthyosis

The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including <i>PNPLA1</i>. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C&#x3e;T; p.Arg298*, family A) and a recurrent missense variant (c.102C&#x3e;A; p.Asp34Glu, family B) in <i>PNPLA1</i> mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of <i>PNPLA1</i> mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.

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