scholarly journals Novel Compound Heterozygous BBS2 and Homozygous MKKS Variants Detected in Chinese Families with Bardet–Biedl Syndrome

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Li Huang ◽  
Limei Sun ◽  
Zhirong Wang ◽  
Songshan Li ◽  
Chonglin Chen ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
High Body Mass Index ◽  
Sex Characteristics ◽  
Compound Heterozygous ◽  
Chinese Families ◽  
Bardet Biedl Syndrome ◽  
Secondary Sex Characteristics ◽  
Whole Exome ◽  
Systemic Manifestations ◽  
Compound Heterozygous Variants

Background. Bardet–Biedl syndrome (BBS) is a rare multisystem developmental disorder. In this study, we report the genetic causes and clinical manifestations in two Chinese families with BBS. Materials and Methods. Two families were recruited in this study. Family A was a four-generation family with four affected and 15 unaffected members participating in the study, and family B was a consanguineous family with one affected and three unaffected members participating. Whole exome sequencing was performed in the two families, followed by a multistep bioinformatics analysis. Sanger sequencing was used to verify the variants and to perform a segregation analysis. Comprehensive ocular and systemic examinations were also conducted. Results. Novel compound heterozygous variants c.235T > G (p.T79P) and c.534 + 1G > T were detected in the BBS2 gene in family A, and known homozygous variant c.748G > A (p.G250R) was detected in the MKKS gene in family B. Both families presented with retinitis pigmentosa; however, except for polydactyly, all other systemic manifestations were different. All of the affected family members in family A were overweight with a high body mass index (range from 26.5 to 41.9) and high blood pressure. Family A also presented with a delay in the onset of secondary sex characteristics and genital anomalies, while other systemic abnormalities were absent in family B. Conclusions. This study presents one family with two novel BBS2 variants, expanding the variant spectrum of BBS, and one family with a known homozygous MKKS variant. The different phenotypes seen between the families with BBS2 and MKKS variants will contribute to the literature and our overall understanding of BBS.

scholarly journals Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aliaa H. Abdelhakim ◽  
Avinash V. Dharmadhikari ◽  
Sara D. Ragi ◽  
Jose Ronaldo Lima de Carvalho ◽  
Christine L. Xu ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Neurological Involvement ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

scholarly journals Clinical case of epilepsy, hearing loss and mental retardation syndrome associated with mutations in SPATA5 gene

2021 ◽  
Vol 13 (1) ◽  
pp. 44-50
Author(s):  
T. V. Kozhanova ◽  
S. S. Zhilina ◽  
T. I. Meshcheryakova ◽  
E. G. Luk’yanova ◽  
K. V. Osipova ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mental Retardation ◽  
Clinical Case ◽  
Clinical Manifestations ◽  
Compound Heterozygous ◽  
Gene Variant ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
Patients With Epilepsy ◽  
Possible Cause

We present the clinical case of patient with epilepsy, developmental retardation and hearing loss. The whole exome sequencing allowed to reveal compound heterozygous variants  of the nucleotide sequence in SPATA5 gene (c.1714+1G>A, c.1678G>A). Mutations in the SPATA5 gene have been described  in patients with epilepsy, hearing loss and mental retardation  syndrome (MIM 616577). Paired parents were carriers of one  heterozygous gene variant. Such mutations lead to the  development of epileptic disorders in 3% of cases, and should be  considered in patients not only as a possible cause of  neurodegenerative diseases, but also leading to pathology with  clinical manifestations mimicking mitochondrial disease. 

Novel Pathogenic Mutations of FERMT1 in two Chinese Kindler Syndrome Families

2021 ◽  
Author(s):  
Min Li ◽  
Weisheng Li ◽  
Dan Zhu ◽  
Likui Lu ◽  
Jingliu Liu ◽  
...  
Keyword(s):  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Nonsense Mutations ◽  
Chinese Families ◽  
Kindler Syndrome ◽  
Pathogenic Mutations ◽  
Whole Exome ◽  
Palmoplantar Hyperkeratosis ◽  
Cigarette Paper

Abstract Background: Kindler syndrome (KNDLRS) is a very rare autosomal recessive disorder characterized by bullous poikiloderma with photosensitivity. Loss-of-function mutations in FERMT1, which located on chromosome 20p12.3, were responsible for KNDLRS. Numerous mutations in FERMT1 have been reported to be associated with KNDLRS. Results: The present study reported two Chinese KNDLRS families, and affected individuals from both families presented with poikiloderma, palmoplantar hyperkeratosis, and diffuse cigarette paper like atrophy on hands. Skin biopsy of the proband from family 2 showed atrophy of epidermis, hyperkeratosis, dilated blood vessels in upper dermis, and microbubbles at the dermis and epidermis junction. Medical Whole Exome Sequencing V4 combined with Sanger sequencing revealed mutations in FERMT1 with affected individuals. Compound heterozygous nonsense mutations (c.193C>T, c.277C>T) were found with family 1, and a homozygous frameshift mutation (c.220delC) was observed in family 2. According to the clinical features and genetic analysis, KNDLRS was diagnosed in two Chinese families. Conclusions: This study revealed two novel pathogenic mutations in FERMT1 that caused KNDLRS and briefly summarized all pathogenic mutations in FERMT1 that have been documented via the PubMed.

Clinical and Pathological Features of a Newborn With Compound Heterozygous ANKS6 Variants

2019 ◽  
Vol 23 (3) ◽  
pp. 235-239
Author(s):  
Sakil Kulkarni ◽  
Brooj Abro ◽  
Maria Laura Duque Lasio ◽  
Janis Stoll ◽  
Dorothy K Grange ◽  
...  
Keyword(s):  
Cardiac Failure ◽  
Renal Dysplasia ◽  
Cardiomyocyte Hypertrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genes Encoding ◽  
Cystic Renal Dysplasia ◽  
Cystic Renal Disease ◽  
Compound Heterozygous Variants

We report a term female infant born to nonconsanguineous parents who presented with renal failure at birth, hypothyroidism, cholestasis, and progressive cardiac dysfunction. Multigene next-generation sequencing panels for cholestasis, cardiomyopathy, and cystic renal disease did not reveal a unifying diagnosis. Whole exome sequencing revealed compound heterozygous pathogenic variants in ANKS6 (Ankyrin Repeat and Sterile Alpha Motif Domain Containing 6), which encodes a protein that interacts with other proteins of the Inv compartment of cilium ( NEK8, NPHP2/INVS, and NPHP3). ANKS6 has been shown to be important for early renal development and cardiac looping in animal models. Autopsy revealed cystic renal dysplasia and cardiomyocyte hypertrophy, disarray, and focal necrosis. Liver histology revealed cholestasis and centrilobular necrosis, which was likely a result of progressive cardiac failure. This is the first report of compound heterozygous variants in ANKS6 leading to a nephronopthisis-related ciliopathy-like phenotype. We conclude that pathogenic variants in ANKS6 may present early in life with severe renal and cardiac failure, similar to subjects with variants in genes encoding other proteins in the Inv compartment of the cilium.

scholarly journals Recurrent respiratory viral diseases and chronic sequelae due to dominant negative IFIH1

2020 ◽  
Author(s):  
Christin L Deal ◽  
Timothy J Thauland ◽  
Rebecca Signer ◽  
Stanley F Nelson ◽  
Hane Lee ◽  
...  
Keyword(s):  
Viral Infections ◽  
Respiratory Infections ◽  
Clinical Manifestations ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Negative Effect ◽  
Respiratory Viral Infections ◽  
Compound Heterozygous Variants

Viral respiratory infections are the most common childhood infection worldwide. However, even common pathogens can have significant consequences in the context of patients with primary immunodeficiency diseases. More than half or viral infections annually are due to rhinovirus/enterovirus strains. Most clinical manifestations of viral infection are mild. However 3% of cases result in hospitalization in patients who have no other known risk factors. These patients may have an inborn error of immunity, a genetic susceptibility to viral infections. Here we present the case of an adult male who suffered respiratory viral infections his whole life and developed chronic, inflammatory damage to sinuses and lungs as a consequence. Genomic sequencing identified compound heterozygous variants in the IFIH1 gene, encoding the protein Melanoma Differentiation Association Protein 5 (MDA5), a RIG-I-like cytoplasmic sensor of RNA intracellular infections. We show a dominant negative effect on these variants on the level of interferon-induced expression of MDA5 protein. This work supports that loss-of-function variants in IFIH1 affect the sensing of viral infections. Underlying genomic variants may dictate the point at which recurrent, respiratory viral infections leave commonplace experience and incur lasting damage.

scholarly journals Case Report: Whole Exome Sequencing Identifies Compound Heterozygous Variants in TSFM Gene Causing Juvenile Hypertrophic Cardiomyopathy

2022 ◽  
Vol 8 ◽  
Author(s):  
Jamie O. Yang ◽  
Hapet Shaybekyan ◽  
Yan Zhao ◽  
Xuedong Kang ◽  
Gregory A. Fishbein ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Elongation Factor ◽  
Nuclear Gene ◽  
Compound Heterozygous ◽  
Mitochondrial Translation ◽  
Translation Elongation ◽  
Whole Exome ◽  
Compound Heterozygous Variants

We report a case of hypertrophic cardiomyopathy and lactic acidosis in a 3-year-old female. Cardiac and skeletal muscles biopsies exhibited mitochondrial hyperplasia with decreased complex IV activity. Whole exome sequencing identified compound heterozygous variants, p.Arg333Trp and p.Val119Leu, in TSFM, a nuclear gene that encodes a mitochondrial translation elongation factor, resulting in impaired oxidative phosphorylation and juvenile hypertrophic cardiomyopathy.

scholarly journals Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Xiao-Hui Wang ◽  
Le Xie ◽  
Sen Chen ◽  
Kai Xu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Bioinformatics Analysis ◽  
Compound Heterozygous ◽  
Congenital Deafness ◽  
Chinese Families ◽  
Novel Variants ◽  
Common Causes ◽  
Compound Heterozygous Variants ◽  
Generation Sequencing

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

scholarly journals Novel HSD17B4 Variants Cause Progressive Leukodystrophy in Childhood: Case Report and Literature Review

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110486
Author(s):  
Akiyo Yamamoto ◽  
Shinobu Fukumura ◽  
Yumi Habata ◽  
Sachiko Miyamoto ◽  
Mitsuko Nakashima ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Brain Magnetic Resonance Imaging ◽  
Compound Heterozygous ◽  
Long Chain Fatty Acids ◽  
Developmental Regression ◽  
Whole Exome ◽  
Uncertain Significance ◽  
Compound Heterozygous Variants ◽  
High Degree ◽  
Moderate Hearing Loss

D-bifunctional protein (DBP) deficiency is a peroxisomal disorder with a high degree of phenotypic heterogeneity. Some patients with DBP deficiency develop progressive leukodystrophy in childhood. We report a 6-year-old boy with moderate hearing loss who presented with developmental regression. Brain magnetic resonance imaging demonstrated progressive leukodystrophy. However, very long chain fatty acids (VLCFAs) in the plasma were at normal levels. Whole-exome sequencing revealed compound heterozygous variants in HSD17B4 (NM_000414.3:c.[350A > T];[394C > T], p.[[Asp117Val]];[[Arg132Trp]]). The c.394C > T variant has been identified in patients with DBP deficiency and is classified as likely pathogenic, while the c.350A > T variant was novel and classified as uncertain significance. Although one of the two variants was classified as uncertain significance, an accumulation of phytanic and pristanic acids was identified in the patient, confirming type III DBP deficiency. DBP deficiency should be considered as a diagnosis in children with progressive leukodystrophy and hearing loss even if VLCFAs are within normal levels.

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