Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35

2020 ◽  
Vol 182 (10) ◽  
pp. 2417-2425
Author(s):  
Joanna Walczak‐Sztulpa ◽  
Anna Wawrocka ◽  
Beata Leszczynska ◽  
Boyana Mikulska ◽  
Heleen H. Arts ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Prenatal Genetic Diagnosis ◽  
Compound Heterozygous Variants

scholarly journals The genotype analysis and prenatal genetic diagnosis among 244 pedigrees with methylmalonic aciduria in China

2021 ◽  
Author(s):  
Shuang Hu ◽  
Lina Liu ◽  
Zhihui Jiao ◽  
Xiangdong Kong
Keyword(s):  
Prenatal Diagnosis ◽  
Chorionic Villus ◽  
Genetic Diagnosis ◽  
Methylmalonic Aciduria ◽  
Compound Heterozygous ◽  
Chorionic Villus Sampling ◽  
Prenatal Genetic Diagnosis ◽  
Heterozygous Variant ◽  
Compound Heterozygous Variants

Abstract To investigate the phenotypes, biochemical features and genotypes for 244 pedigrees with methylmalonic aciduria (MMA) in China, and to perform the prenatal genetic diagnosis by chorionic villus for these pedigrees. Gene analyses were performed for 244 pedigrees. There are 130 families, chorionic villus sampling was performed on the pregnant women to conduct the prenatal diagnosis. Among 244 patients, 168 (68.9%) cases were combined methylmalonic aciduria and homocystinuria, 76 (31.1%) cases were isolated methymalonic aciduria. All the patients were diagnosed with MMA by their clinical manifestation, elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and/or urine/blood methylmalonic acid with or without hyperhomocysteinemia. MMACHC, MUT, SUCLG1 and LMBRD1 gene variants were found in 236 (96.7%) pedigrees included 6 probands with only one heterozygous variant out of 244 cases. For the 130 pedigrees who received a prenatal diagnosis, 22 foetuses were normal, 69 foetuses were carriers of heterozygous variants, and the remaining 39 foetuses harboured compound heterozygous variants or homozygous variants. The follow-up results were consistent with the prenatal diagnosis. The present study indicates genetic heterogeneity in MMA patients. Genetic analysis is a convenient method for prenatal diagnosis that will aid in avoiding the delivery of MMA patients.

scholarly journals Mutation analysis and prenatal diagnosis of 419 cases of Spinal Muscular Atrophy in China

2020 ◽  
Author(s):  
YingJie Sun ◽  
Xiangdong Kong ◽  
Xuechao Zhao ◽  
Zhenhua Zhao
Keyword(s):  
Prenatal Diagnosis ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Chorionic Villus ◽  
Genetic Diagnosis ◽  
Point Mutations ◽  
Homozygous Deletion ◽  
Compound Heterozygous ◽  
Prenatal Genetic Diagnosis ◽  
Compound Heterozygous Variants

Abstract Background Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disease, which is caused by mutations of the survival motor neuron 1 (SMN1) gene. At present, the gene therapy medicine for SMA, i.e. , Spinraza (Nusinersen), has been approved by the FDA, bringing hope to SMA patients and families. In this study, we analyzed the deletion of SMN gene in patients suspected of SMA, and performed prenatal genetic diagnosis of SMA. Methods In this study, we collected the peripheral blood of 419 probands and their parents who were treated in the genetic counseling clinic at our hospital from January 2010 to September 2019, and extracted DNA from the blood samples for analysis. Patients who were diagnosed with SMA were first tested by MLPA. The patients with negative MLPA results were further analysed with long-range PCR combined with nest PCR and validated by Sanger sequencing to look for point mutations. In 293 families, pregnant women were subjected to chorionic villus or amniotic fluid sampling for prenatal genetic diagnosis depending on gestational weeks. In addition to the above methods used for genetic diagnosis, we also used QF-PCR in all prenatal diagnoses, which can help detect the presence of trisomy of chromosome while eliminating maternal contamination. Results 1. Homozygous deletion of SMN1 exon 7 was detected in 96.40% (404/419) of patients. Homozygous deletion of SMN1 exon 7 alone was detected in 15 patients (3.60%). 2. In total, 10 point mutations were detected in the 15 pedigrees. Five of these variants have not been previously reported in the literature. 3. Among the 293 pedigrees that underwent one prenatal diagnosis, 118 foetuses were normal, 149 foetuses were carriers of heterozygous variants, and the remaining 72 foetuses harboured compound heterozygous variants or homozygous variants. 4. In all prenatal diagnoses, we found one 21-trisomy fetus by QF-PCR. Couples whose foetuses were normal or carriers continued the pregnancy, whereas couples whose foetuses harboured compound heterozygous variants or homozygous variants decided to terminate the pregnancy. The follow-up results were consistent with the prenatal diagnosis.

scholarly journals Tyrosinase gene mutations in the Chinese Han population with OCA1

2014 ◽  
Vol 96 ◽  
Author(s):  
NING LIU ◽  
XIANG DONG KONG ◽  
HUI RONG SHI ◽  
QING HUA WU ◽  
MIAO JIANG
Keyword(s):  
At Risk ◽  
Genetic Disorder ◽  
Severe Disease ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Oculocutaneous Albinism ◽  
Compound Heterozygous ◽  
Chinese Han ◽  
Essential Information ◽  
Prenatal Genetic Diagnosis

SummaryOculocutaneous albinism (OCA) is a heterogeneous autosomal recessive genetic disorder that affects melanin synthesis. OCA results in reduced or absent pigmentation in the hair, skin and eyes. Type 1 OCA (OCA1) is the result of tyrosinase (TYR) gene mutations and is a severe disease type. This study investigated TYR mutations in a Chinese cohort with OCA1. This study included two parts: patient genetic study and prenatal genetic diagnosis. A total of 30 OCA1 patients were subjected to TYR gene mutation analysis. Ten pedigrees were included for prenatal genetic diagnosis. A total of 100 unrelated healthy Chinese individuals were genotyped for controls. The coding sequence and the intron/exon junctions of TYR were analysed by bidirectional DNA sequencing. In this study, 20 mutations were identified, four of which were novel. Of these 30 OCA1 patients, 25 patients were TYR compound heterozygous; two patients carried homozygous TYR mutations; and three were heterozygous. Among the ten prenatally genotyped fetuses, three fetuses carried compound heterozygous mutations and seven carried no mutation or only one mutant allele of TYR and appeared normal at birth. In conclusion, we identified four novel TYR mutations and showed that molecular-based prenatal screening to detect TYR mutations in a fetus at risk for OCA1 provided essential information for genetic counselling of couples at risk.

scholarly journals Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Qi Tian ◽  
Yang Cao ◽  
Li Shu ◽  
Yongjun Chen ◽  
Ying Peng ◽  
...  
Keyword(s):  
Brain Mri ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Molybdenum Cofactor ◽  
Compound Heterozygous ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
First Case ◽  
Healthy Family ◽  
Compound Heterozygous Variants

Background: The molybdenum cofactor (Moco) deficiency in humans results in the inactivity of molybdenum-dependent enzymes and is caused by pathogenic variants in MOCS1 (Molybdenum cofactor synthesis 1), MOCS2 (Molybdenum cofactor synthesis 2), and GPHN (Gephyrin). These genes along with MOCS3 (Molybdenum cofactor synthesis 3) are involved in Moco biosynthesis and providing cofactors to Moco-dependent enzymes. Until now, there was no study to confirm that MOCS3 is a causative gene of Moco deficiency.Methods: Detailed clinical information was collected in the pedigree. The Whole-exome sequencing (WES) accompanied with Sanger sequencing validation were performed.Results: We described the clinical presentations of an infant, born to a non-consanguineous healthy family, diagnosed as having MOCS3 variants caused Moco deficiency and showing typical features of Moco deficiency including severe neurologic symptoms and cystic encephalomalacia in the brain MRI, resulting in neonatal death. Compound heterozygous variants in the MOCS3 gene were identified by WES. Positive sulfite and decreased levels of uric acid in plasma and urine were detected.Conclusion: To our knowledge, this is the first case of MOCS3 variants causing Moco deficiency. Our study may contribute to genetic diagnosis of Moco deficiency and future genetic counseling.

scholarly journals Identification of novel deep intronic PAH gene variants in patients with phenylketonuria

2021 ◽  
Author(s):  
Xiaohua Jin ◽  
Yousheng Yan ◽  
Chuan Zhang ◽  
Ya Tai ◽  
Lisha An ◽  
...  
Keyword(s):  
Phenylalanine Hydroxylase ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Gene Variants ◽  
Structural Variants ◽  
Splice Site Selection ◽  
Reverse Transcription Pcr ◽  
Compound Heterozygous Variants ◽  
Pah Gene ◽  
Dependent Probe

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) gene variants. Previously, 94.21% of variants were identified using Sanger sequencing and multiplex ligation-dependent probe amplification. To investigate the remaining variants, whole-genome sequencing (WGS) was performed in four patients with PKU with unknown genotype to identify deep intronic or structural variants. Three novel heterozygous variants (c.706+368T>C; c.1065+241C>A; and c.1199+502A>T) were identified in a deep PAH gene intron. The c.1199+502A>T variant was detected in 60% (6/10) PKU patients. In silico prediction showed that the three deep variants may impact splice site selection and result in inclusion of a pseudo-exon. The c.1199+502A>T PAH minigene and reverse transcription PCR of blood RNA in a patient with PKU and compound heterozygous variants (c.1199+502A>T/ c.1199G>A) confirmed that the c.1199+502A>T variant creates a novel branch point and leads to the inclusion of a 25 bp in PAH mRNA (r.1199_2000ins1199+538_1199+562). Furthermore, the c.1199G>A mutation leads to the retention of an additional 17 nt in the PAH mRNA transcript (r.1199_2000ins1199+1_1199+17). These results expand the PAH genotypic spectrum and highlight that deep intronic analysis of PAH can improve genetic diagnosis in undiagnostic patients.

scholarly journals GRID – Genomics of Rare Immune Disorders: a highly sensitive and specific diagnostic gene panel for patients with primary immunodeficiencies

2018 ◽  
Author(s):  
Ilenia Simeoni ◽  
Olga Shamardina ◽  
Sri VV Deevi ◽  
Moira Thomas ◽  
Karyn Megy ◽  
...  
Keyword(s):  
Copy Number Variants ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Immune Disorders ◽  
Single Nucleotide Variants ◽  
Bioinformatics Pipeline ◽  
Highly Sensitive ◽  
Compound Heterozygous Variants ◽  
Sensitivity Specificity

AbstractPrimary Immune disorders affect 15,000 new patients every year in Europe. Genetic tests are usually performed on a single or very limited number of genes leaving the majority of patients without a genetic diagnosis. We designed, optimised and validated a new clinical diagnostic platform called GRID, Genomics of Rare Immune Disorders, to screen in parallel 279 genes, including 2015 IUIS genes, known to be causative of Primary Immune disorders (PID). Validation to clinical standard using more than 58,000 variants in 176 PID patients shows an excellent sensitivity, specificity. The customised and automated bioinformatics pipeline prioritises and reports pertinent Single Nucleotide Variants (SNVs), INsertions and DELetions (INDELs) as well as Copy Number Variants (CNVs). An example of the clinical utility of the GRID panel, is represented by a patient initially diagnosed with X-linked agammaglobulinemia due to a missense variant in the BTK gene with severe inflammatory bowel disease. GRID results identified two additional compound heterozygous variants in IL17RC, potentially driving the altered phenotype.

scholarly journals Novel Compound Heterozygous PRKN Variants in a Han-Chinese Family with Early-Onset Parkinson’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Kuan Fan ◽  
Pengzhi Hu ◽  
Chengyuan Song ◽  
Xiong Deng ◽  
Jie Wen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Early Onset ◽  
Genetic Factors ◽  
Genetic Diagnosis ◽  
Han Chinese ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Compound Heterozygous Variants ◽  
Early Onset Parkinson’S Disease

Genetic factors are thought to play an important role in the pathogenesis of Parkinson’s disease (PD), particularly early-onset PD. The PRKN gene is the primary disease-causing gene for early-onset PD. The details of its functions remain unclear. This study identified novel compound heterozygous variants (p.T240K and p.L272R) of the PRKN gene in a Han-Chinese family with early-onset PD. This finding is helpful in the genetic diagnosis of PD and also the functional research of the PRKN gene.

Atypical Clinical Presentation of Persistent Müllerian Duct Syndrome in Siblings

2021 ◽  
pp. 1-6
Author(s):  
Evgenia Globa ◽  
Nataliya Zelinska ◽  
Nina Siryk ◽  
Anu Bashamboo ◽  
Kenneth McElreavey
Keyword(s):  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Normal Male ◽  
Compound Heterozygous ◽  
Mullerian Duct ◽  
Müllerian Duct ◽  
Persistent Müllerian Duct Syndrome ◽  
Persistent Mullerian Duct Syndrome ◽  
Bilateral Cryptorchidism ◽  
Duct Syndrome

Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder characterized by the lack of regression of the derivatives of the Müllerian ducts in males. Boys with this condition usually present with unilateral or bilateral cryptorchidism, inguinal hernias, and reproductive disorders with normal male genitalia. Variants in the AMH or AMHR2 genes are responsible for the development of this syndrome. The genetic diagnosis and surgery in PMDS is challenging for both the endocrinologist and the urologist. Here, we describe the management of 2 siblings from 1 family who presented with bilateral cryptorchidism and hypospadias at birth. One child had testis located in the pelvis in the position of normal ovaries, while the other child had testis which were located in the inguinal canals (bilateral inguinal cryptorchidism). Exome sequencing revealed a compound heterozygous variant in the AMHR2 gene c.1388G>A, p.R463H and c.1412G>A p.R471H. To our knowledge, hypospadias has not been described in association with PMDS.

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