scholarly journals Ataxia and hypogonadotropic hypogonadism with intrafamilial variability caused by RNF216 mutation

2016 ◽  
Vol 8 (2) ◽  
Author(s):  
Mohammed Alqwaifly ◽  
Saeed Bohlega
Keyword(s):  
Splice Site ◽  
Autosomal Recessive ◽  
Hypogonadotropic Hypogonadism ◽  
Distinct Phenotype ◽  
Splicing Variant ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
Whole Exome ◽  
Novel Variants ◽  
Intrafamilial Variability

Gordon Holmes syndrome (GHS) is a distinct phenotype of autosomal recessive cerebellar ataxia, characterized by ataxia, dementia, reproductive defects and hypogonadism; it has been recently found to be associated with <em>RNF216</em> mutation. We performed whole-exome sequencing and filtered the resulting novel variants by the coordinates of the shared autozygome. We identified a novel splicing variant in <em>RNF216</em> that is likely to abolish the canonical splice site at the junction of exon/intron 13 (NM_207111.3:c.2061G&gt;A). We herein report two patients with GHS caused by a novel <em>RNF216</em> mutation as the first follow up report on <em>RNF216</em>-related GHS, and <em>show</em> interfamilial variability of phenotype supporting the previously reported RNF216-related cases.

scholarly journals Novel MYO15A Variants are Associated with Hearing Loss in the Two Iranian Pedigrees

2020 ◽  
Author(s):  
somayeh khatami ◽  
Masomeh Askari ◽  
Fatemeh Bahreini ◽  
Morteza Hashemzadeh Chaleshtori ◽  
Saeed Hematian ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Clinical Genetic ◽  
Clinical Evaluations ◽  
Large Size ◽  
Whole Exome ◽  
Novel Variants ◽  
Syndromic Hearing Loss ◽  
Traditional Approaches

Abstract Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods.Methods: This study was a report on two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results: The implementation of WES to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) and its related variants was reported in the present study. Two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 were correspondingly identified and then segregations were confirmed using Sanger sequencing. According to online prediction tools, both identified variants seemed to have damaging effects.Conclusion: This study further supported the effectiveness of WES for genetic diagnosis of ARNSHL as a first approach.

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 Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

2022 ◽  
Author(s):  
Zhidan Hong ◽  
Xuanyi He ◽  
Fang Yu ◽  
Huanyu Liu ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Pathological Examination ◽  
Compound Heterozygous ◽  
Over Expression ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
Novel Variant ◽  
Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

scholarly journals Genetic analysis of osteopetrosis in Pakistani families identifies novel and known sequence variants

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chunyu Liu ◽  
Muhammad Ajmal ◽  
Zaineb Akram ◽  
Tariq Ghafoor ◽  
Muhammad Farhan ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Whole Exome ◽  
Novel Variants ◽  
Malignant Osteopetrosis ◽  
The Stability ◽  
Pakistani Families ◽  
Infantile Malignant Osteopetrosis

AbstractOsteopetrosis is a genetically heterogenous, fatal bone disorder characterized by increased bone density. Globally, various genetic causes are reported for osteopetrosis with all forms of inheritance patterns. A precise molecular diagnosis is necessary for prognosis and for prescribing treatment paradigms in osteopetrosis. Here we report on thirteen individuals diagnosed with infantile malignant osteopetrosis coming from ten unrelated Pakistani families; nine of whom are consanguineous. We performed whole exome sequencing and Sanger sequencing in all families and identified homozygous variants in genes previously reported for autosomal recessive inheritance of osteopetrosis. All the identified variants are expected to affect the stability or length of gene products except one nonsynonymous missense variant. TCIRG1 was found as a candidate causal gene in majority of the families. We report six novel variants; four in TCIRG1 and one each in CLCN7 and OSTM1. Our combined findings will be helpful in molecular diagnosis and genetic counselling of patients with osteopetrosis particularly in populations with high consanguinity.

scholarly journals A splice-site variant (c.3289-1G>T) in OTOF underlies profound hearing loss in a Pakistani kindred

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ashfaque Ahmed ◽  
Meng Wang ◽  
Rizwan Khan ◽  
Abid Ali Shah ◽  
Hui Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Splice Site ◽  
Full Range ◽  
Disease Phenotype ◽  
Profound Hearing Loss ◽  
Splicing Variant ◽  
Whole Exome ◽  
High Prevalence ◽  
Splicing Variants ◽  
Splice Site Variant

Abstract Background Hearing loss/deafness is a common otological disorder found in the Pakistani population due to the high prevalence of consanguineous unions, but the full range of genetic causes is still unknown. Methods A large consanguineous Pakistani kindred with hearing loss was studied. Whole-exome sequencing and Sanger sequencing were performed to search for the candidate gene underlying the disease phenotype. A minigene assay and reverse transcription polymerase chain reaction was used to assess the effect of splicing variants. Results The splicing variants of OTOF (NM_194248, c.3289-1G>T) cosegregated with the disease phenotype in this Pakistani family. The substitution of a single base pair causes the deletion of 10 bp (splicing variant 1) or 13 bp (splicing variant 2) from exon 27, which results in truncated proteins of 1141 and 1140 amino acids, respectively. Conclusion Our findings reveal an OTOF splice-site variant as pathogenic for profound hearing loss in this family.

scholarly journals A Splice-site Variant (C.3289-1G>T) in OTOF Underlies Profound Hearing Loss in a Pakistani Kindred

2020 ◽  
Author(s):  
ashfaque ahmed ◽  
Meng Wang ◽  
Rizwan Khan ◽  
Abid Ali Shah ◽  
Hui Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Splice Site ◽  
Full Range ◽  
Disease Phenotype ◽  
Profound Hearing Loss ◽  
Splicing Variant ◽  
Whole Exome ◽  
High Prevalence ◽  
Splicing Variants ◽  
Splice Site Variant

Abstract Background: Hearing loss/deafness is a common otological disorder found in the Pakistani population due to the high prevalence of consanguineous unions, but the full range of genetic causes is still unknown.Methods: A large consanguineous Pakistani kindred with hearing loss was studied. Whole-exome sequencing and Sanger sequencing were performed to search for the candidate gene underlying the disease phenotype. A minigene assay and reverse transcription polymerase chain reaction were used to assess the effect of splicing variants.Results: The splicing variants of OTOF (NM_194248, c.3289-1G>T) cosegregated with the disease phenotype in this Pakistani family. The substitution of a single base pair causes the deletion of 10 bp (splicing variant 1) or 13 bp (splicing variant 2) from exon 27, which results in truncated proteins of 1141 and 1140 amino acids, respectively.Conclusion: Our findings reveal an OTOF splice-site variant as pathogenic for profound hearing loss in this family.

scholarly journals Long Term Follow-Up of Polish Patients with Isovaleric Aciduria. Clinical and Molecular Delineation of Isovaleric Aciduria

Diagnostics ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 738
Author(s):  
Edyta Szymańska ◽  
Aleksandra Jezela-Stanek ◽  
Anna Bogdańska ◽  
Dariusz Rokicki ◽  
Ewa Ehmke vel Emczyńska-Seliga ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Autosomal Recessive ◽  
Clinical State ◽  
Neurological Outcomes ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Long Term Follow Up ◽  
Isovaleric Aciduria

Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children’s Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients’ medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one—severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients.

scholarly journals Two Novel Mutations in the SI Gene Associated With Congenital Sucrase-Isomaltase Deficiency: A Case Report in China

2021 ◽  
Vol 9 ◽  
Author(s):  
Jianli Zhou ◽  
Yuzhen Zhao ◽  
Xia Qian ◽  
Yongwei Cheng ◽  
Huabo Cai ◽  
...  
Keyword(s):  
Case Report ◽  
Autosomal Recessive ◽  
Chronic Diarrhea ◽  
Failure To Thrive ◽  
Inherited Disease ◽  
Restricted Diet ◽  
Novel Mutations ◽  
Case Presentation ◽  
Whole Exome ◽  
Novel Variants

Background: Congenital sucrase-isomaltase deficiency (CSID) is an autosomal recessive inherited disease that leads to the maldigestion of disaccharides and is associated with mutation of the sucrase-isomaltase (SI) gene. Cases of CSID are not very prevalent in China or worldwide but are gradually being identified and reported.Case Presentation: We report a case involving a 14-month-old male who presented with failure to thrive that had begun after food diversification and was admitted for chronic diarrhea. We used a whole-exome sequencing (WES) approach to identify mutations in this patient's genome. WES revealed two novel heterozygous mutations in the SI gene, c.2626C &gt; T (p.Q876*) and c.2872C &gt; T (p.R958C), which were confirmed by Sanger DNA sequencing. With a strict sucrose- and starch-restricted diet, the patient's diarrhea was resolved, and he began to gain weight.Conclusions: We report a case of novel variants in the SI gene that caused CSID. This report provides valuable information for the clinical field, especially in China.

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