Novel Compound Heterozygous Variants in the CDC6 Gene in a Russian Patient with Meier-Gorlin Syndrome

AbstractWe report a case of a 13-year-old boy with arginase 1 deficiency carrying a new variant in ARG1. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G>A (p.Trp122*)/c.820G>A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.

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Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

BMC Medical Genomics ◽

10.1186/s12920-021-00911-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Carla De Angelis ◽

Alicia B. Byrne ◽

Rebecca Morrow ◽

Jinghua Feng ◽

Thuong Ha ◽

...

Keyword(s):

Cortical Development ◽

Occipital Cortex ◽

Compound Heterozygous ◽

Valuable Insight ◽

Periventricular Nodular Heterotopia ◽

Case Presentation ◽

Malformation Of Cortical Development ◽

Nodular Heterotopia ◽

Compound Heterozygous Variants ◽

Insight Into

Abstract Background Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. Case presentation We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3. LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. Conclusion We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.

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Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽

10.3390/genes12071053 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1053

Author(s):

Jasleen Dhaliwal ◽

Ying Qiao ◽

Kristina Calli ◽

Sally Martell ◽

Simone Race ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Variable Effect ◽

Gabaergic Neurotransmission ◽

High Heritability ◽

Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

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Neonatal-Onset Familial Mediterranean Fever in an Infant with Human Parainfluenza Virus-4 Infection

Neonatology ◽

10.1159/000514694 ◽

2021 ◽

pp. 1-5

Author(s):

Alexandre Michev ◽

Alessandro Borghesi ◽

Caterina Tretti ◽

Maddalena Martella ◽

Amelia Di Comite ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Parainfluenza Virus ◽

Compound Heterozygous ◽

Inborn Errors ◽

Immunological Responses ◽

Inflammatory Conditions ◽

Neonatal Onset ◽

Mediterranean Fever ◽

Compound Heterozygous Variants ◽

Human Parainfluenza Virus

Unusual, severe infections or inflammatory episodes in newborns and infants are largely unexplained and often attributed to immature immune responses. Inborn errors of immunity (IEI) are increasingly recognized as the etiology of life-threatening inflammatory and infectious diseases in infancy. We describe a patient with a unique neonatal-onset Familial Mediterranean Fever (FMF) due to compound heterozygous variants in <i>MEFV</i>, presenting as pleuritis following human parainfluenza virus-4 infection. Diagnostic challenges of FMF in infancy include the interpretation of the attacks as infectious episodes. Newborns and infants with acute, recurrent, or chronic, unusually severe infectious or inflammatory conditions should be screened for IEI, including both disorders with defective immunological responses and autoinflammatory disorders.

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

Bioscience Reports ◽

10.1042/bsr20193443 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

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.

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Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis

Frontiers in Genetics ◽

10.3389/fgene.2021.719624 ◽

2021 ◽

Vol 12 ◽

Author(s):

Katalin Komlosi ◽

Olivier Claris ◽

Sophie Collardeau-Frachon ◽

Julia Kopp ◽

Ingrid Hausser ◽

...

Keyword(s):

Phenotypic Variability ◽

Heart Tissue ◽

Organ Involvement ◽

Compound Heterozygous ◽

Diagnostic Challenge ◽

Second Child ◽

Dilatative Cardiomyopathy ◽

Collodion Baby ◽

Fatal Course ◽

Compound Heterozygous Variants

Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis. DOLK-CDG is such a rare subtype, resulting from a defect in dolichol kinase, in which the congenital skin phenotype (often ichthyosis) is later associated with variable extracutaneous features such as dilatative cardiomyopathy, epilepsy, microcephaly, visual impairment, and hypoglycemia and may lead to a fatal course. We report two neonatal cases of lethal ichthyosis from the same family, with distal digital constrictions and a progressive course leading to multi-organ failure and death. Postmortem trio whole-exome sequencing revealed the compound heterozygous variants NM_014908.3: c.1342G>A, p.(Gly448Arg) and NM_014908.3: c.1558A>G, p.(Thr520Ala) in the DOLK gene in the first affected child, which were confirmed in the affected sibling. Reduced staining with anti-α-Dystroglycan antibody was observed in frozen heart tissue of the second child as an expression of reduced O-mannosylation due to the dolichol kinase deficiency. In addition to the detailed dermatopathological changes, both cases presented hepatic and extrahepatic hemosiderosis on histological examination. Our patients represent an early and fatal form of DOLK-CDG with a striking presentation at birth resembling severe collodion baby. Both cases emphasize the phenotypic variability of glycosylation disorders and the importance to broaden the differential diagnosis of ichthyosis and to actively search for organ involvement in neonates with ichthyosis.

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A Survey of Compound Heterozygous Variants in Pediatric Cancers and Structural Birth Defects

Frontiers in Genetics ◽

10.3389/fgene.2021.640242 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dustin B. Miller ◽

Stephen R. Piccolo

Keyword(s):

Heart Defects ◽

Disorders Of Sex Development ◽

Compound Heterozygous ◽

Healthy Population ◽

Alternative Mechanism ◽

Disease Development ◽

Data Resource ◽

Sex Development ◽

Gene Copies ◽

Compound Heterozygous Variants

Compound heterozygous (CH) variants occur when two recessive alleles are inherited and the variants are located at different loci within the same gene in a given individual. CH variants are important contributors to many different types of recessively inherited diseases. However, many studies overlook CH variants because identification of this type of variant requires knowing the parent of origin for each nucleotide. Using computational methods, haplotypes can be inferred using a process called “phasing,” which estimates the chromosomal origin of most nucleotides. In this paper, we used germline, phased, whole-genome sequencing (WGS) data to identify CH variants across seven pediatric diseases (adolescent idiopathic scoliosis: n = 16, congenital heart defects: n = 709, disorders of sex development: n = 79, ewing sarcoma: n = 287, neuroblastoma: n = 259, orofacial cleft: n = 107, and syndromic cranial dysinnervation: n = 172), available as parent-child trios in the Gabriella Miller Kids First Data Resource Center. Relatively little is understood about the genetic underpinnings of these diseases. We classified CH variants as “potentially damaging” based on minor allele frequencies (MAF), Combined Annotation Dependent Depletion scores, variant impact on transcription or translation, and gene-level frequencies in the disease group compared to a healthy population. For comparison, we also identified homozygous alternate (HA) variants, which affect both gene copies at a single locus; HA variants represent an alternative mechanism of recessive disease development and do not require phasing. Across all diseases, 2.6% of the samples had a potentially damaging CH variant and 16.2% had a potentially damaging HA variant. Of these samples with potentially damaging variants, the average number of genes per sample was 1 with a CH variant and 1.25 with a HA variant. Across all samples, 5.1 genes per disease had a CH variant, while 35.6 genes per disease had a HA variant; on average, only 4.3% of these variants affected common genes. Therefore, when seeking to identify potentially damaging variants of a putatively recessive disease, CH variants should be considered as potential contributors to disease development. If CH variants are excluded from analysis, important candidate genes may be overlooked.

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