Acromesomelic dysplasia-Maroteaux type, nine patients with two novel NPR2 variants

Abstract Objectives Acromesomelic dysplasia, type Maroteaux, is an autosomal recessive skeletal dysplasia caused by biallelic loss of function variations of NPR2, which encodes a cartilage regulator C-type natriuretic peptide receptor B. NPR2 variations impair skeletal growth. It is a rare type of dwarfism characterized by shortening of the middle and distal segments of the limbs with spondylar dysplasia. Methods We performed detailed clinical and radiological evaluation and sequence analysis for NPR2. Results Herein, we report nine patients from eight families with two novel NPR2 pathogenic variants. Conclusions This study describes typical clinical phenotypes of Maroteaux type acromesomelic dysplasia, and enriches the variant spectrum of NPR2 by reporting one nonsense and one missense novel variant. We emphasize the importance of detailed clinical evaluation before genetic testing in diagnosing rare skeletal disorders.

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Spondylocarpotarsal synostosis syndrome due to a novel loss of function FLNB variant: a case report

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03890-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Samina Yasin ◽

Outi Makitie ◽

Sadaf Naz

Keyword(s):

Short Stature ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Loss Of Function ◽

Case Presentation ◽

Pathogenic Variants ◽

Skeletal Malformations ◽

Tarsal Bones ◽

The Family ◽

Heterozygous Carriers

Abstract Background Loss of function or gain of function variants of Filamin B (FLNB) cause recessive or dominant skeletal disorders respectively. Spondylocarpotarsal synostosis syndrome (SCT) is a rare autosomal recessive disorder characterized by short stature, fused vertebrae and fusion of carpal and tarsal bones. We present a novel FLNB homozygous pathogenic variant and present a carrier of the variant with short height. Case presentation We describe a family with five patients affected with skeletal malformations, short stature and vertebral deformities. Exome sequencing revealed a novel homozygous frameshift variant c.2911dupG p.(Ala971GlyfsTer122) in FLNB, segregating with the phenotype in the family. The variant was absent in public databases and 100 ethnically matched control chromosomes. One of the heterozygous carriers of the variant had short stature. Conclusion Our report expands the genetic spectrum of FLNB pathogenic variants. It also indicates a need to assess the heights of other carriers of FLNB recessive variants to explore a possible role in idiopathic short stature.

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A Loss-of-Function Mutation in Natriuretic Peptide Receptor 2 (Npr2) Gene Is Responsible for Disproportionate Dwarfism incn/cnMouse

Journal of Biological Chemistry ◽

10.1074/jbc.c500024200 ◽

2005 ◽

Vol 280 (14) ◽

pp. 14288-14292 ◽

Cited By ~ 97

Author(s):

Takehito Tsuji ◽

Tetsuo Kunieda

Keyword(s):

Natriuretic Peptide ◽

Natriuretic Peptide Receptor ◽

Loss Of Function ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor 2

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The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

10.1101/2020.11.16.384206 ◽

2020 ◽

Author(s):

Hila Fridman ◽

Helger G. Yntema ◽

Reedik Mägi ◽

Reidar Andreson ◽

Andres Metspalu ◽

...

Keyword(s):

Intellectual Disabilities ◽

Genetic Architecture ◽

Autosomal Recessive ◽

Genetic Disorder ◽

Pathogenic Variants ◽

Specific Effects ◽

Genome Wide ◽

Wide Scale ◽

Skeletal Disorders ◽

European Populations

AbstractThe number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 exome-sequences of healthy, genetically-unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal recessive (AR) genes, and that 0.8-1% of European couples are at-risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins, but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

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Novel Loss-of-Function Mutations in COCH Cause Autosomal Recessive Nonsyndromic Deafness

10.1101/2020.04.30.071134 ◽

2020 ◽

Cited By ~ 1

Author(s):

Kevin T Booth ◽

Amama Ghaffar ◽

Muhammad Rashid ◽

Luke T Hovey ◽

Mureed Hussain ◽

...

Keyword(s):

Hearing Loss ◽

Rna Splicing ◽

Autosomal Recessive ◽

Dominant Negative ◽

Nonsyndromic Hearing Loss ◽

Loss Of Function ◽

Functional Studies ◽

Pathogenic Variants ◽

Exon Splicing ◽

Coding Variants

AbstractCOCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used mini-gene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA-splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA-splicing, and highlights the need to investigate the effect of coding variants on RNA-splicing.

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Reply: A homozygous GDAP2 loss-of-function variant in a patient with adult-onset cerebellar ataxia; and Novel GDAP2 pathogenic variants cause autosomal recessive spinocerebellar ataxia-27 (SCAR27) in a Chinese family

Brain ◽

10.1093/brain/awaa122 ◽

2020 ◽

Vol 143 (6) ◽

pp. e51-e51

Author(s):

Ilse Eidhof ◽

Jonathan Baets ◽

Erik-Jan Kamsteeg ◽

Annette Schenck ◽

Bart P van de Warrenburg

Keyword(s):

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

Autosomal Recessive ◽

Chinese Family ◽

Adult Onset ◽

Loss Of Function ◽

Pathogenic Variants

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Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00272.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. E1339-E1348 ◽

Cited By ~ 57

Author(s):

Takei Kake ◽

Hidetomo Kitamura ◽

Yuichiro Adachi ◽

Tetsuro Yoshioka ◽

Tomoyuki Watanabe ◽

...

Keyword(s):

Natriuretic Peptide ◽

Guanylyl Cyclase ◽

Natriuretic Peptides ◽

Critical Role ◽

Skeletal Growth ◽

Heart Weight ◽

Receptor Subtype ◽

Natriuretic Peptide Receptor ◽

High Concentration ◽

Peptide Receptor

C-type natriuretic peptide (CNP) plays a critical role in endochondral ossification through guanylyl cyclase-B (GC-B), a natriuretic peptide receptor subtype. Cartilage-specific overexpression of CNP enhances skeletal growth and rescues the dwarfism in a transgenic achondroplasia model with constitutive active mutation of fibroblast growth factor receptor-3. For future clinical application, the efficacy of CNP administration on skeletal growth must be evaluated. Due to the high clearance of CNP, maintaining a high concentration is technically difficult. However, to model high blood CNP concentration, we established a liver-targeted CNP-overexpressing transgenic mouse (SAP-CNP tgm). SAP-CNP tgm exhibited skeletal overgrowth in proportion to the blood CNP concentration and revealed phenotypes of systemic stimulation of cartilage bones, including limbs, paws, costal bones, spine, and skull. Furthermore, in SAP-CNP tgm, the size of the foramen magnum, the insufficient formation of which results in cervico-medullary compression in achondroplasia, also showed significant increase. CNP primarily activates GC-B, but under high concentrations it cross-reacts with guanylyl cyclase-A (GC-A), a natriuretic peptide receptor subtype of atrial natriuretic peptides (ANP) and brain natriuretic peptides (BNP). Although activation of GC-A could alter cardiovascular homeostasis, leading to hypotension and heart weight reduction, the skeletal overgrowth phenotype in the line of SAP-CNP tgm with mild overexpression of CNP did not accompany decrease of systolic blood pressure or heart weight. These results suggest that CNP administration stimulates skeletal growth without adverse cardiovascular effect, and thus CNP could be a promising remedy targeting achondroplasia.

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Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

Molecular Case Studies ◽

10.1101/mcs.a006130 ◽

2021 ◽

pp. mcs.a006130

Author(s):

Ryan J Patrick ◽

Jill M Weimer ◽

Laura Davis-Keppen ◽

Megan L Landsverk

Keyword(s):

Intellectual Disability ◽

Autosomal Recessive ◽

Missense Variant ◽

Facial Features ◽

Loss Of Function ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

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Three Novel Variants of CEP290 and CC2D2DA and a Link Between ZNF77 and SHH Signaling Pathway Are Found in Two Meckel-Gruber Syndrome Fetuses

Reproductive Sciences ◽

10.1007/s43032-021-00835-5 ◽

2022 ◽

Author(s):

Zhidan Hong ◽

Xuanyi He ◽

Fang Yu ◽

Huanyu Liu ◽

Xiaoli Zhang ◽

...

Keyword(s):

Autosomal Recessive ◽

Pathological Examination ◽

Compound Heterozygous ◽

Over Expression ◽

Pathogenic Variants ◽

Whole Exome ◽

The Family ◽

Novel Variants ◽

Novel Variant ◽

Missed Diagnosis

AbstractMeckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive inherited disorder. Missed diagnosis might happen in clinical works due to an unclear genotype–phenotype correlation. We analyzed two families visiting our center; the parents are normal; each of the family aborted a fetus at 12WG. Following ultrasonography and pathological examination, both were diagnosed as MKS. Whole exome sequencing identified a compound heterozygous of two novel variants of CEP290 and a heterozygous of a novel variant of CC2D2A. Frameshift mutations in ZNF77 were also detected. Western blot analyzing whole-brain tissue showed that the expression of ZNF77, CC2D2A, and CEP290 was enhanced. HEK293T transfected with over-expression wildtype/mutated ZNF77 plasmid showed that SHH was increased in wildtype ZNF77 cells, while SHH and CC2D2A were increased in mutated ZNF77 cells. Our research provided two novel pathogenic variants of CEP290 and CC2D2A and suggested that ZNF77 might promote the expression of CC2D2A and regulate the amount of SHH.

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SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia

Neurology Genetics ◽

10.1212/nxg.0000000000000478 ◽

2020 ◽

Vol 6 (4) ◽

pp. e478 ◽

Cited By ~ 3

Author(s):

Tommy Stödberg ◽

Måns Magnusson ◽

Nicole Lesko ◽

Anna Wredenberg ◽

Daniel Martin Munoz ◽

...

Keyword(s):

Autosomal Recessive ◽

Neurodevelopmental Disorder ◽

Brain Mri ◽

Autosomal Recessive Inheritance ◽

Recessive Inheritance ◽

Inheritance Pattern ◽

Loss Of Function ◽

Pathogenic Variants ◽

Gastrointestinal Problems ◽

Life Threatening

ObjectiveTo describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS).MethodsAfter an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their parents was performed, and potentially pathogenic variants were analyzed.ResultsThe proband and her older sister both presented with neonatal Staphylococcus aureus parotitis, apneas, disappearance of the Moro reflex, and hypotonia. The proband survived. Her brain MRI showed white matter and basal ganglia abnormalities, and CSF damage biomarkers were increased. At age 8 years, she exhibits a constellation of symptoms including severe neurodevelopmental disorder, hearing impairment, gastrointestinal problems, and a striking lack of tear fluid, saliva, and sweat. Her respiratory mucosa is dry with potentially life-threatening mucus plugging. Through WGS, 2 loss-of-function variants in SLC12A2 were identified that follow an autosomal recessive inheritance pattern.ConclusionsTaken together with a single previously reported case and the close resemblance to the phenotypes of corresponding mouse models, our study firmly establishes biallelic variants in SLC12A2 as causing human disease and adds data regarding the neurologic phenotype.

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