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. 

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.

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 Whole-exome sequencing as a powerful tool for identifying genetic causes in a patient with POLG-related disorders and phenylketonuria

2019 ◽  
Vol 47 (3) ◽  
pp. 1387-1394 ◽  
Author(s):  
Lin Li ◽  
Jin-Qi Zhao ◽  
Chengrong Wang ◽  
Nan Yang ◽  
Li-Fei Gong ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Mental Retardation ◽  
Liver Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Genetic Causes ◽  
Whole Exome ◽  
Compound Heterozygous Mutations

Objective This study’s aim was to identify the genetic causes in a patient with phenylketonuria and hearing loss, liver disease, developmental and mental retardation, hypotonia, and external ophthalmoplegia. Methods Whole-exome sequencing and Sanger sequencing analysis were used to determine the genetic causes of manifestations in a young boy with hearing loss, liver disease, develop-mental and mental retardation, hypotonia, and external ophthalmoplegia. Results We found that the child harbored polymerase gamma ( POLG) compound heterozygous mutations, c.2617G>A (p.E873K) and c.3550G>A (p.D1184N), and phenylalanine hydroxylase ( PAH) compound heterozygous mutations, c.721C>T (p.R241C) and c.728G>A (p.R243Q). Among them, the POLG p.E873K mutation is a novel mutation and is not present in the Exome Aggregation Consortium database, Genome Aggregation database, and 1000 Genomes database. The two heterozygous mutations were each inherited from both of the child’s parents. This finding suggested that the phenotype and the genotype were segregated. Conclusion Using whole-exome sequencing, we not only identified PAH mutations causing phenylketonuria, but also identified the genetic cause of the mitochondrial disease and found a novel POLG mutation. Our findings could be useful in helping future parents obtain healthy embryos through assisted reproductive technology.

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 Cochlear Implantation in a Patient with a Novel POU3F4 Mutation and Incomplete Partition Type-III Malformation

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Xiuhua Chao ◽  
Yun Xiao ◽  
Fengguo Zhang ◽  
Jianfen Luo ◽  
Ruijie Wang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cochlear Implantation ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Bioinformatic Analysis ◽  
Chinese Family ◽  
Whole Exome ◽  
Novel Variant ◽  
Genetic Features ◽  
The Right

Aims. This study is aimed at (1) analyzing the clinical manifestations and genetic features of a novel POU3F4 mutation in a nonsyndromic X-linked recessive hearing loss family and (2) reporting the outcomes of cochlear implantation in a patient with this mutation. Methods. A patient who was diagnosed as the IP-III malformation underwent cochlear implantation in our hospital. The genetic analysis was conducted in his family, including the whole-exome sequencing combined with Sanger sequencing and bioinformatic analysis. Clinical features, preoperative auditory and speech performances, and postoperative outcomes of cochlear implant (CI) were assessed on the proband and his family. Results. A novel variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was detected in the family, which was cosegregated with the hearing loss. This variant was absent in 200 normal-hearing persons. The phylogenetic analysis and structure modeling of Pou3f4 protein further confirmed that the novel mutation was pathogenic. The proband underwent cochlear implantation on the right ear at four years old and gained greatly auditory and speech improvement. However, the benefits of the CI declined about three and a half years postoperation. Though the right ear had been reimplanted, the outcomes were still worse than before. Conclusion. A novel frame shift variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was identified in a Chinese family with X-linked inheritance hearing loss. A patient with this mutation and IP-III malformation could get good benefits from CI. However, the outcomes of the cochlear implantation might decline as the patient grows old.

scholarly journals A novel LOXHD1 variant in a Chinese couple with hearing loss

2019 ◽  
Vol 47 (12) ◽  
pp. 6082-6090 ◽  
Author(s):  
Chuan Zhang ◽  
Shengju Hao ◽  
Yali Liu ◽  
Bingbo Zhou ◽  
Furong Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Diagnosis ◽  
Protein Function ◽  
Mexican American ◽  
Compound Heterozygous ◽  
Congenital Hearing Loss ◽  
Targeted Next Generation Sequencing ◽  
Novel Variants ◽  
Novel Variant ◽  
Compound Heterozygous Variants

Objective To perform molecular diagnosis and genetic counseling in a young Chinese couple with congenital hearing loss. Methods Variant screening analysis was performed by PCR and direct Sanger sequencing or targeted next-generation sequencing of all known hearing loss genes. Novel variants were evaluated by PolyPhen2 and PROVEAN software tools to evaluate possible effects on protein function. Results We identified causative variants in the young couple: c.235delC (rs80338943)/c.299-300delAT (rs111033204) compound heterozygous variants of GJB2 in the husband and c.1828G>A (p.Glu610Lys, rs535637788)/c.2825-2827delAGA compound heterozygous variants of LOXHD1 in the wife. The LOXHD1 c.1828G>A variant has only previously been reported in a Mexican-American individual in the 1000 Genomes Project database. Using PolyPhen2 and PROVEAN, we speculated that the LOXHD1 variant c.1828G>A is potentially pathogenic. Conclusion We carried out molecular diagnosis in a young couple with congenital hearing loss, and identified different disease-causing genes in the two individuals. The LOXHD1 variant c.1828G>A present in the wife had not previously been reported in individuals with congenital hearing loss. We determined this to be a potential pathogenic variant, and a novel variant associated with hearing loss in a Chinese individual.

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 Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: late diagnosis and gender reassignment in a two-year-old child

2021 ◽  
Vol 67 (5) ◽  
pp. 53-57
Author(s):  
N. Yu. Raygorodskaya ◽  
E. P. Novikova ◽  
A. N. Tyulpakov ◽  
M. A. Kareva ◽  
N. A. Nikolaeva ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Case ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Gender Reassignment ◽  
And Gender ◽  
21 Hydroxylase Deficiency

11β-hydroxylase deficiency is a rare autosomal recessive disorder due to impaired steroidogenesis in the adrenal cortex caused by pathogenic mutations in the CYP11B1 gene. The main clinical manifestations are determined by a deficiency of cortisol, ACTH hyperproduction, excessive androgens secretion and the accumulation of 11-deoxycorticosterone, which leads to the development of arterial hypertension. In the diagnostic search, it is important to take into account the ethnicity of the patient, since the frequency of the disease and the prevalence of mutations differ between ethnic groups. The article presents a clinical case of 11β-hydroxylase deficiency as the result of compound heterozygous mutations in the CYP11B1 gene in a patient of Turkic origin. This case shows the clinical manifestations and the development of complications of 11β-hydroxylase deficiency, the stages of differential diagnosis of patients with 21-hydroxylase deficiency.

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