Hemorrhagic shock and encephalopathy syndrome in a patient with a de novo heterozygous variant in KIF1A

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

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A Novel Intronic Pathogenic Variant in STAR With a Dominant Negative Mechanism Causes Attenuated Lipoid Congenital Adrenal Hyperplasia

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211014685 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110146

Author(s):

Erin Finn ◽

Kimberly Kripps ◽

Christina Chambers ◽

Michele Rapp ◽

Naomi J. L. Meeks ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Autosomal Recessive ◽

De Novo ◽

Dominant Negative ◽

Adrenal Hyperplasia ◽

Primary Adrenal Insufficiency ◽

Heterozygous Variant ◽

Novel Variant ◽

Autosomal Recessive Condition ◽

Clinically Significant

Lipoid congenital adrenal hyperplasia (LCAH) is typically inherited as an autosomal recessive condition. There are 3 reports of individuals with a dominantly acting heterozygous variant leading to a clinically significant phenotype. We report a 46,XY child with a novel heterozygous intronic variant in STAR resulting in LCAH with an attenuated genital phenotype. The patient presented with neonatal hypoglycemia and had descended testes with a fused scrotum and small phallus. Evaluation revealed primary adrenal insufficiency with deficiencies of cortisol, aldosterone, and androgens. He was found to have a de novo heterozygous novel variant in STAR: c.65-2A>C. We report a case of a novel variant and review of other dominant mutations at the same position in the literature. Clinicians should be aware of the possibility of attenuated genital phenotypes of LCAH and the contribution of de novo variants in STAR at c.65-2 to the pathogenesis of that phenotype.

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Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

Journal of Neonatology ◽

10.1177/09732179211068815 ◽

2022 ◽

pp. 097321792110688

Author(s):

Francisco Ribeiro-Mourão ◽

Ana Vilan ◽

Sara Passos-Silva ◽

Fernando Silveira ◽

Miguel Leão ◽

...

Keyword(s):

De Novo ◽

Bone Fractures ◽

Muscular Atrophy ◽

Hip Dislocation ◽

Arthrogryposis Multiplex Congenita ◽

Pathogenic Variants ◽

Genetic Abnormalities ◽

Heterozygous Variant ◽

Fetal Movements ◽

Intrafamilial Variability

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

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Abstract P477: A Novel SMYD1 Variant (c.302A>G) Leads To Dilated Cardiomyopathy And Biventricular Heart Failure.

Circulation Research ◽

10.1161/res.129.suppl_1.p477 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Marta Szulik ◽

Miguel Reyes-Mugica ◽

Daniel F Marker ◽

Lina Ghaloul-Gonzalez ◽

Sarah Franklin

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Cardiac Tissue ◽

De Novo ◽

Cardiac Development ◽

Left Ventricular ◽

Histopathological Analysis ◽

Loss Of Function ◽

Adult Mice ◽

Heterozygous Variant

The lysine methyltransferase SMYD1 was first identified in mice and shown to be important for embryonic cardiac development. Subsequently, we reported the first analysis of SMYD1 in adult myocardium and demonstrated that cardiomyocyte-specific loss of SMYD1 lead to progressive cardiac hypertrophy and heart failure, and showed that this enzyme is necessary to maintain metabolic homeostasis through transcriptional regulation of mitochondrial energetics in adult mice. While SMYD1 has been the subject of several additional studies in zebrafish and mice, since it was first identified, only in the last few years have human patients been identified with variants in the SMYD1 gene thought to be responsible for their cardiomyopathies. Specifically, two patients have been identified to date, the first patient displaying hypertrophic cardiomyopathy had a de novo heterozygous variant (c.814T>C) and the second patient with left ventricular non-compaction cardiomyopathy and arrhythmias had a truncating heterozygous variant (c.675delA). Here we report a third patient with biventricular heart failure containing a homozygous variant (c.302A>G; p.Asn101S) in the SMYD1 gene which was identified by a whole exome sequencing. Our histopathological analysis of cardiac tissue and skeletal muscle from the proband showed abnormalities in myofibrillar organization in both cardiac and skeletal muscle suggesting that SMYD1 is necessary for sarcomere assembly and organization. In addition, we observe markedly abnormal myocardium with extensive fibrosis and multifocal calcification, and our ultrastructural (EM) analysis revealed presence of abnormal mitochondria with reduced and irregular or lost cristae. Lastly, we have performed structural modeling of SMYD1 containing the p.Asn101Ser variant (N101S) and report how this variant may affect the enzymatic activity of SMYD1 due to its proximity to the substrate binding site. The identification of this novel variant constitutes the third patient with a SMYD1 variant displaying cardiomyopathy and provides insights into the molecular functionality of this protein. In addition, this is the first analysis of tissue from a patient expressing a SMYD1 variant which provides critical insights into the role of SMYD1 in the heart and how loss of function mutations can effect cardiac physiology.

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A Novel De Novo TUBB3 Variant Causing Developmental Delay, Epilepsy and Mild Ophthalmological Symptoms in a Chinese Child.

10.21203/rs.3.rs-660033/v1 ◽

2021 ◽

Author(s):

Jiao Xue ◽

Zhenfeng Song ◽

Shuyin Ma ◽

Zhi Yi ◽

Chengqing Yang ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Febrile Seizures ◽

Extraocular Muscles ◽

Global Developmental Delay ◽

Missense Mutations ◽

Brain Malformations ◽

Heterozygous Variant ◽

Type 3 ◽

Congenital Fibrosis

Abstract Heterozygous missense mutations in TUBB3 have been implicated in various neurological disorders encompassing either isolated congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or complex cortical dysplasia with other brain malformations 1 (CDCBM1). The description of seizures in patients with TUBB3 mutations is rare. Here, we reported a patient who had febrile seizures before and focal seizure this time, which was diagnosed as epilepsy in combination with an abnormal EEG. MRI showed hypoplastic corpus callosum. Mutation analysis showed a novel de novo heterozygous variant of TUBB3 gene (NM_006086), c.763G>A (p.V255I). He had global developmental delay, photophobia and elliptic pupil, but lacking extraocular muscles involvement and malformations of cortical development, which might be a less severe phenotype of TUBB3 mutations. This was the first report of elliptic pupil in patients with TUBB3 mutations and expanded the spectrum of TUBB3 phenotypes. It indicated that the phenotypic range of TUBB3 mutations might be more continuous than discrete, with a severity ranging from mild to severe. Further studies are needed to elucidate the complete spectrum of TUBB3-related phenotypes.

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A De Novo Heterozygous Variant (HBB: c.379delG, p.Val127Cysfs*32) Associated with a Mild β-Thalassemia Intermedia Phenotype in a Turkish Child

Hemoglobin ◽

10.1080/03630269.2019.1660888 ◽

2019 ◽

Vol 43 (4-5) ◽

pp. 277-279

Author(s):

Dilek Gürlek-Gökçebay ◽

Sibel Akpinar-Tekgunduz ◽

Haktan B. Erdem ◽

Nese Yarali

Keyword(s):

De Novo ◽

Thalassemia Intermedia ◽

Turkish Child ◽

Heterozygous Variant

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Severe Generalized Epidermolysis Bullosa Simplex in Two Hong Kong Children due to De Novo Variants in KRT14 and KRT5

Case Reports in Pediatrics ◽

10.1155/2020/4206348 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Shuk Ching Chong ◽

Kam Lun Hon ◽

Fernando Scaglia ◽

Chung Mo Chow ◽

Yu Ming Fu ◽

...

Keyword(s):

Hong Kong ◽

Epidermolysis Bullosa ◽

De Novo ◽

Genetic Diagnosis ◽

Recurrence Risk ◽

Severe Form ◽

Epidermolysis Bullosa Simplex ◽

First Case ◽

Heterozygous Variant ◽

History Of

We report two Hong Kong children with severe generalized epidermolysis bullosa simplex (EBS), the most severe form of EBS, without a family history of EBS. EBS is a rare genodermatosis usually inherited in an autosomal dominant fashion although rare autosomal recessive cases have been reported. Genetic studies in these patients showed that the first case was due to a novel de novo heterozygous variant, c.377T>G (NM_000526.5 (c.377T>G, p.Leu126Arg)) in the KRT14 gene and the second case was due to a rare de novo heterozygous variant c.527A>G (NM_000424.4, c.527A>G, p.Asn176Ser) in the KRT5 gene. To our knowledge, the c.377T>G variant in the KRT14 gene has not been previously reported, and the c.527A>G variant in the KRT5 gene is a rare cause of severe generalized EBS. In severe generalized EBS, infants exhibit severe symptoms at the onset; however, they tend to improve with time. A precise genetic diagnosis in these two cases aided in counseling the families concerning the prognosis in their affected children and the recurrence risk for future pregnancies.

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De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

Molecular Brain ◽

10.1186/s13041-021-00838-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Robin N. Stringer ◽

Bohumila Jurkovicova-Tarabova ◽

Ivana A. Souza ◽

Judy Ibrahim ◽

Tomas Vacik ◽

...

Keyword(s):

Ion Channel ◽

De Novo ◽

Epileptic Encephalopathy ◽

Gene Encoding ◽

Epileptic Encephalopathies ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Whole Exome ◽

Heterozygous Variant

AbstractDevelopmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

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‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

Acta Endocrinologica ◽

10.1530/eje-19-0472 ◽

2020 ◽

Vol 182 (1) ◽

pp. K1-K6 ◽

Cited By ~ 1

Author(s):

Yunting Lin ◽

Yanna Cai ◽

Jianan Xu ◽

Chunhua Zeng ◽

Huiying Sheng ◽

...

Keyword(s):

Sanger Sequencing ◽

De Novo ◽

Hypophosphatemic Rickets ◽

Dominant Inheritance ◽

Germline Mosaicism ◽

Pathogenic Variants ◽

First Case ◽

Heterozygous Variant ◽

The Family ◽

Normal Father

Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

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