scholarly journals Case Report: Prenatal Diagnosis of a Fetus With Harlequin Ichthyosis Identifies Novel Compound Heterozygous Variants: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiao Liu ◽  
Xingyu Zhang ◽  
Weilan Wang ◽  
Xiaofang Lan ◽  
Minyue Dong ◽  
...  
Keyword(s):  
Case Report ◽  
Soft Tissues ◽  
Severe Form ◽  
Whole Body ◽  
Chromosomal Microarray ◽  
Compound Heterozygous ◽  
Chromosomal Microarray Analysis ◽  
Pathogenic Variants ◽  
Harlequin Ichthyosis ◽  
Compound Heterozygous Variants

BackgroundHarlequin ichthyosis (HI) is the most severe form of the keratinizing disorders, and it is characterized by whole-body hard stratum corneum. ABCA12 has been identified as the major disease-causing gene of HI.MethodsA case of HI was prenatally diagnosed by ultrasonography and genetic tests. The fetus had been found with dentofacial deformity and profound thickening of the palm and plantar soft tissues. Chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were then performed on the amniotic fluid to identify germline pathogenic variants for the fetus. Candidate variants were verified by Sanger sequencing.ResultsCompound heterozygous frameshift variants (p.Q719QfsX21; p.F2286LfsX6) of ABCA12 were identified for the fetus, suggesting the former variants were maternally inherited and the latter paternally inherited. The fetus was terminated.ConclusionA prenatal molecular diagnosis is an important approach for the prevention of HI. In the study, we provided a successful case of genetic counseling for a family with an HI baby.

scholarly journals Case Report: Compound Heterozygous Variants of SLC13A3 Identified in a Chinese Patient With Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Qingyun Kang ◽  
Liming Yang ◽  
Hongmei Liao ◽  
Sai Yang ◽  
Haiyang Yang ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Case Report ◽  
Chinese Patient ◽  
Compound Heterozygous ◽  
Genetic Studies ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Chinese Girl ◽  
Febrile Episodes ◽  
Compound Heterozygous Variants

Background:SLC13A3 gene encodes the Na+/dicarboxylate cotransporter 3 (NaDC3), which locates on the plasma membrane and is mainly expressed in kidney, astrocytes and the choroid plexus. It imports four to six carbon dicarboxylates together with three Na+ ions into the cytosol. Nowadays, pathogenic variants of SLC13A3 gene were found to cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation (ARLIAK) in patients. Here, we report two novel SLC13A3 variants c.185C>T (p.T62M) and c.331C>T (p.R111*) identified in a Chinese patient with ARLIAK.Case Presentation: The patient was a Chinese girl aged 13 years and 7 months old, who had acute, recurrent neurological deterioration during two febrile episodes. She presented with reversible leukoencephalopathy and increased urinary excretion of α-ketoglutarate. Genetic studies revealed compound heterozygous variants (c.185C>T, p.T62M, and c.331C>T, p.R111*) in SLC13A3, which had not been reported previously.Conclusions: These findings expand the variant spectrum of SLC13A3, providing the basis for the further study of this rare disease.

scholarly journals Clinical characterization of chromosome 5q21.1–21.3 microduplication: A case report

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 1123-1127
Author(s):  
Shuang Chen ◽  
Yang Yu ◽  
Han Zhang ◽  
Leilei Li ◽  
Yuting Jiang ◽  
...  
Keyword(s):  
Case Report ◽  
Microarray Analysis ◽  
Prenatal Testing ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Chromosome 5 ◽  
Left Lateral Ventricle ◽  
Pulsed Doppler Ultrasound

AbstractChromosomal microdeletions and microduplications likely represent the main genetic etiologies for children with developmental delay or intellectual disability. Through prenatal chromosomal microarray analysis, some microdeletions or microduplications can be detected before birth to avoid unnecessary abortions or birth defects. Although some microdeletions or microduplications of chromosome 5 have been reported, numerous microduplications remain undescribed. We describe herein a case of a 30-year-old woman carrying a fetus with a chromosome 5q21.1–q21.3 microduplication. Because noninvasive prenatal testing indicated a fetal chromosome 5 abnormality, the patient underwent amniocentesis at 22 weeks 4 days of gestation. Karyotyping and chromosomal microarray analysis were performed on amniotic fluid cells. Fetal behavioral and structural abnormalities were assessed by color and pulsed Doppler ultrasound. Clinical characteristics of the newborn were assessed during the follow-up. The left lateral ventricle appeared widened on ultrasound, but the infant appeared normal at birth. The 5q21.1–q21.3 microduplication in the fetus was inherited from his mother. There are seven genes in this duplication region, but their main functions are unclear. According to this case report, microduplication in this region could represent a benign mutation. Clinicians should pay attention to the breakpoints and the genes involved when counseling patients with microdeletions and microduplications.

scholarly journals Novel compound heterozygous EYS variants may be associated with arRP in a large Chinese pedigree

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Chunli Wei ◽  
Ting Xiao ◽  
Jingliang Cheng ◽  
Jiewen Fu ◽  
Qi Zhou ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Gene Mutations ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
The Novel ◽  
Pathogenic Variants ◽  
Pathogenic Genes ◽  
Compound Heterozygous Variants ◽  
Normal Controls

Abstract As a genetically heterogeneous ocular dystrophy, gene mutations with autosomal recessive retinitis pigmentosa (arRP) in patients have not been well described. We aimed to detect the disease-causing genes and variants in a Chinese arRP family. In the present study, a large Chinese pedigree consisting of 31 members including a proband and another two patients was recruited; clinical examinations were conducted; next-generation sequencing using a gene panel was used for identifying pathogenic genes, and Sanger sequencing was performed for verification of mutations. Novel compound heterozygous variants c.G2504A (p.C835Y) and c.G6557A (p.G2186E) for the EYS gene were identified, which co-segregated with the clinical RP phenotypes. Sequencing of 100 ethnically matched normal controls didn’t found these mutations in EYS. Therefore, our study identified pathogenic variants in EYS that may cause arRP in this Chinese family. This is the first study to reveal the novel mutation in the EYS gene (c.G2504A, p.C835Y), extending its mutation spectrum. Thus, the EYS c.G2504A (p.C835Y) and c.G6557A (p.G2186E) variants may be the disease-causing missense mutations for RP in this large arRP family. These findings should be helpful for molecular diagnosis, genetic counseling and clinical management of arRP disease.

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 Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 967
Author(s):  
Mohamed H. Al-Hamed ◽  
Nada Alsahan ◽  
Maha Tulbah ◽  
Wesam Kurdi ◽  
Wafa’a I. Ali ◽  
...  
Keyword(s):  
Developmental Disorder ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Facial Features ◽  
Chromosomal Microarray Analysis ◽  
Speech Delay ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Antenatal Sonography ◽  
First Time

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. Methods and Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. Conclusions: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period.

scholarly journals Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy

2020 ◽  
Vol 6 (5) ◽  
pp. e505
Author(s):  
Rodrigo de Holanda Mendonça ◽  
Ciro Matsui ◽  
Graziela Jorge Polido ◽  
André Macedo Serafim Silva ◽  
Leslie Kulikowski ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Copy Number ◽  
Clinical Phenotype ◽  
Muscular Atrophy ◽  
Large Population ◽  
Survival Motor Neuron ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Exon 1 ◽  
Compound Heterozygous Variants

ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

scholarly journals Fetal Akinesia Deformation Sequence (FADS) with Compound Heterozygous Variants in MuSK: a Case Report

2020 ◽  
Author(s):  
Lina Ding ◽  
Yinong Xie ◽  
Tingting Yuan ◽  
Zhen Sui ◽  
Hongzhou Liu ◽  
...  
Keyword(s):  
Case Report ◽  
Compound Heterozygous ◽  
Compound Heterozygous Variants

scholarly journals Novel MFSD8 Variants in a Chinese Family with Nonsyndromic Macular Dystrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Qin Xiang ◽  
Yanna Cao ◽  
Hongbo Xu ◽  
Zhijian Yang ◽  
Liang Tang ◽  
...  
Keyword(s):  
Family Members ◽  
Major Facilitator Superfamily ◽  
Chinese Family ◽  
Macular Dystrophy ◽  
Compound Heterozygous ◽  
The Novel ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants ◽  
Major Facilitator ◽  
Mfsd8 Gene

Purpose. To identify the molecular etiology of a Chinese family with nonsyndromic macular dystrophy. Methods. Ophthalmic examinations were performed, and genomic DNA was extracted from available family members. Whole exome sequencing of two members (the proband and her unaffected mother) and Sanger sequencing in available family members were performed to screen potential pathogenic variants. Results. Novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the major facilitator superfamily domain containing 8 gene (MFSD8) were suspected to be involved in this family’s macular dystrophy phenotype. The novel c.1066C>T variant in the MFSD8 gene probably resulted in substitution of serine for proline at the 356th residue and was predicted to be “uncertain significance” through in silico analyses. The novel c.1102+2T>C variant in the MFSD8 gene was likely to affect the splicing form and predicted to be “pathogenic.” Conclusion. The novel compound heterozygous variants, c.1066C>T (p.Pro356Ser) and c.1102+2T>C, in the MFSD8 gene are likely responsible for the isolated macular dystrophy phenotype in this family. This study enlarged the MFSD8 gene mutant spectrum and might provide more accurate genetic counseling for this family.

scholarly journals Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Niu Li ◽  
Yufei Xu ◽  
Yi Zhang ◽  
Guoqiang Li ◽  
Tingting Yu ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Atrioventricular Canal ◽  
Multiple Systems ◽  
Feeding Difficulties ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Compound Heterozygous Variants

Abstract Background Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture. Methods Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies. Results Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in the ERBB3 gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways. Conclusions We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants of ERBB3.

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).

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