PIK3R1 Mutation Associated with Hyper IgM (APDS2 Syndrome): A Case Report and Review of the Literature

Background and Objective: APDS [Activated phosphoinositide 3-kinase (PI3K) δ Syndrome] is a newly found special form of primary immunodeficiency caused by mutations in genes encoding PI3Kδ subunits and over-activation of the PI3K signaling pathway. Gain-of-function and loss-of-function mutations in PIK3CD (encoding P110δ) and PIK3R1 (encoding p85α, p55α and p50α) lead to APDS1 and APDS2, respectively. The subsequent irregular PI3K downstream signaling cascade is associated with abnormalities in B cells and T cells and the consequent heterogeneous clinical manifestations including respiratory tract infections, autoimmunity, lymphoproliferation and not to mention primary antibody deficiency. In this study, we report a 12-year-old girl with a mutation in the PIK3R1 gene who manifested immunological phenotypes resembling hyper IgM syndrome along with a review of the literature of the previously reported patients. Methods: Whole exome sequencing was performed to detect the underlying genetic mutation in this patient. Results: A de novo heterozygous splice site mutation in the hot spot of the PIK3R1 gene within the intron 10 was found (c.1425+1G>A). Conclusion: Further investigations are required for evaluation of the underlying genetic defects and the possible associations between genetic underpinning and heterogeneous severity and features of the disease.

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Novel mutation in the COL11A1 gene causing Marshall-Stickler syndrome in three generations of a Bulgarian family

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2021-0001 ◽

2021 ◽

Vol 24 (1) ◽

pp. 95-98

Author(s):

M Mladenova ◽

T Todorov ◽

L Grozdanova ◽

V Mitev ◽

A Todorova

Keyword(s):

Splice Site ◽

Novel Mutation ◽

Hot Spot ◽

Clinical Manifestations ◽

Splice Site Mutation ◽

Saddle Nose ◽

Stickler Syndrome ◽

Site Mutation ◽

Three Generations ◽

The Family

Abstract Here we report the first familial case spread through at least three generations, genetically verified cases of Marshall-Stickler syndrome in Bulgaria. The proband, a 2-year-old girl, has craniofacial dysplasia, ocular hypertelorism, small saddle nose with a flat bridge and midface hypoplasia. The pedigree of the proband’s family showed that her father has the same clinical manifestations of the disease. In addition, her father presented with a tall, thin stature and mild hearing loss, manifested with aging. The same dysmorphological symptoms were presented by the paternal grandfather. Both patients, the 2-year-old girl and her father, have been diagnosed to carry Marshall-Stickler syndrome. The COL2A1 gene tested negative in the family. Based on the higher percentage of mutations in the COL2A1 gene, we analyzed this gene as the first target in the family. The COL2A1 gene tested negative, and we sequenced the gene further. A novel splice site mutation c.3474+1G>A was found in intron 44. This variant is related to the clinical presentation in the patient and her father. The c.3474+1G>A mutation results in altered splicing affects at the donor splice site of intron 44, which most probably gives a nonfunctional protein. The variant affects the major triple-helical domain that represents a mutation hot-spot for the gene.

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Four New Cases of SLC35A2-CDG With Novel Mutations and Clinical Features

Frontiers in Genetics ◽

10.3389/fgene.2021.658786 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kuerbanjiang Abuduxikuer ◽

Jian-She Wang

Keyword(s):

Clinical Features ◽

De Novo ◽

Stop Codon ◽

Positive Family History ◽

Premature Stop Codon ◽

Splice Site Mutation ◽

Genetic Mutation ◽

Site Mutation ◽

Rare Type ◽

Han Ethnicity

SLC35A2-CDG is a rare type of X-linked CDG with more than 60 reported cases. We retrospectively analyzed clinical phenotypes and SLC35A2 genotypes of four cases of SLC35A2-CDG from four unrelated families of Han ethnicity in China. All patients had infantile onset epilepsies that were completely or partly resistant to multiple anti-epileptic medications or ketogenic diet. Three patients had severe developmental delay. All patients were female patients carrying de novo deleterious mutations in SLC35A2 (NM_001042498.2) gene, including one canonical splice-site mutation (c.426+1G > A), one large deletion (c.-322_c.274+1del), and two frameshift mutations leading to premature stop codon (c.781delC/p.Arg289ValfsTer88 and c.601delG/p.Ala201GlnfsTer148). Novel clinical features in some of our patients include anemia, hypertriglyceridemia, hypertonia, small ears, extra folds on earlobes, and maternal oligohydramnios or hypothyroidism during pregnancy. In one patient, concomitant Marfan syndrome was confirmed for having positive family history, carrying a heterozygous known disease-causing mutation in FBN1 gene (c.7240C > T/p.Arg2414Ter), and presence of typical features (rachnodactyly, ventrical septal defect, and mitral valve regurgitation). In conclusion, we expanded clinical phenotype and genetic mutation spectrum of SLC35A2-CDG by reporting four new cases with novel pathogenic variants and novel clinical features.

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Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

International Journal of Molecular Sciences ◽

10.3390/ijms22073786 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3786

Author(s):

Andreas Brodehl ◽

Alexey Meshkov ◽

Roman Myasnikov ◽

Anna Kiseleva ◽

Olga Kulikova ◽

...

Keyword(s):

Medical History ◽

Splice Site Mutation ◽

Pathogenic Mutation ◽

Large Deletion ◽

Loss Of Function ◽

Arrhythmogenic Cardiomyopathy ◽

Site Mutation ◽

Snp Arrays ◽

Number Of Patients ◽

History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

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A de novo COL17A1 splice-site mutation causing a 7-bp deletion in a Taiwanese patient with junctional epidermolysis bullosa

European Journal of Dermatology ◽

10.1684/ejd.2021.4011 ◽

2021 ◽

Vol 31 (2) ◽

pp. 267-269

Author(s):

Ping-Chen Hou ◽

Wei-Ting Tu ◽

Peng-Chieh Chen ◽

Bryan Edgar K. Guevara ◽

Yu-Fen Yen ◽

...

Keyword(s):

Splice Site ◽

Epidermolysis Bullosa ◽

De Novo ◽

Splice Site Mutation ◽

Site Mutation ◽

Junctional Epidermolysis Bullosa ◽

Taiwanese Patient

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A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

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Early diagnosis of a newborn with tuberous sclerosis caused by a genetic mutation

Journal of International Medical Research ◽

10.1177/03000605211035895 ◽

2021 ◽

Vol 49 (8) ◽

pp. 030006052110358

Author(s):

Lin Qiao ◽

Yuting Yang ◽

Dongmei Yue

Keyword(s):

Genetic Testing ◽

Early Diagnosis ◽

Tuberous Sclerosis ◽

De Novo ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Heterozygous Mutation ◽

Loss Of Function ◽

Autosomal Dominant Disorder ◽

Tsc1 Gene

Objective Tuberous sclerosis (TSC) is an autosomal dominant disorder, often detected during childhood. We present the results of genetic testing in a newborn with suspected TSC. Methods A newborn with no specific clinical manifestations of TSC showed evidence of TSC on magnetic resonance imaging and echocardiography. Next-generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA) of the TSC1 and TSC2 gene exons were carried out to confirm the diagnosis. Results The results of MLPA were negative, but NGS showed a heterozygous mutation in the TSC1 gene comprising insertion of a T residue at c.2165 (exon 17) to c.2166 (exon 17), indicating a loss of function mutation. These results were verified by Sanger sequencing. This genetic change was present in the newborn but the parental genotypes were wild-type, indicating a de novo mutation. Conclusions In this case, a case of TSC caused by a heterozygous mutation in the TSC1 gene was confirmed by NGS sequencing. This indicates the suitability of genetic testing for the early diagnosis of clinically rare and difficult-to-diagnose diseases, to guide clinical treatment.

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ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9

Nature Communications ◽

10.1038/s41467-019-12428-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Marie F. Smeland ◽

Conor McClenaghan ◽

Helen I. Roessler ◽

Sanne Savelberg ◽

Geir Åsmund Myge Hansen ◽

...

Keyword(s):

Intellectual Disability ◽

Cardiac Dysfunction ◽

Systolic Dysfunction ◽

Splice Site Mutation ◽

Cerebral White Matter ◽

Sulfonylurea Receptor ◽

Loss Of Function ◽

Mild Intellectual Disability ◽

Site Mutation ◽

Gain Of Function

Abstract Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

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Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399401003878 ◽

2001 ◽

Vol 3 (29) ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Tahir Tellioglu ◽

David Robertson

Keyword(s):

Orthostatic Intolerance ◽

Clinical Manifestations ◽

Synaptic Cleft ◽

Norepinephrine Transporter ◽

Genetic Mutation ◽

Clinical Syndrome ◽

Loss Of Function ◽

Direct Association ◽

Type Gene

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.

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