31 research outputs found
Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes
Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in CEP104, CROCC, NEK1, TOM1L2, and TSTD2 predicted as damaging were found to be shared between the four tall family members. Three of the five genes (CEP104, CROCC, and NEK1) belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes
Case report: a novel deep intronic splice-altering variant in DMD as a cause of Becker muscular dystrophy
We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291–13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD
Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism
Broadening the spectrum of loss-of-function variants in NPR-C-related extreme tall stature
CONTEXT: Natriuretic peptide receptor-C (NPR-C, encoded by NPR3) belongs to a family of cell membrane–integral proteins implicated in various physiological processes, including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), that stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in CNP, NPR2, and NPR3 may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia. OBJECTIVE: Here we report on a boy with 2 novel biallelic inactivating variants of NPR3. METHODS: History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants. RESULTS: We identified 2 novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention. CONCLUSION: With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature
An activating deletion variant in the submembrane region of natriuretic peptide receptor-B causes tall stature
CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). DESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant. RESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B. CONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production
An Activating Deletion Variant in the Submembrane Region of Natriuretic Peptide Receptor-B Causes Tall Stature
CONTEXT: C-type natriuretic peptide (CNP) is critically involved in endochondral bone growth. Variants in the genes encoding CNP or its cyclic guanosine monophosphate (cGMP)-forming receptor (natriuretic peptide receptor-B [NPR-B], gene NPR2) cause monogenic growth disorders. Here we describe a novel gain-of-function variant of NPR-B associated with tall stature and macrodactyly of the great toes (epiphyseal chondrodysplasia, Miura type). DESIGN: History and clinical characteristics of 3 family members were collected. NPR2 was selected for sequencing. Skin fibroblasts and transfected HEK-293 cells were used to compare mutant versus wild-type NPR-B activities. Homology modeling was applied to understand the molecular consequences of the variant. RESULTS: Mother's height was +2.77 standard deviation scores (SDS). The heights of her 2 daughters were +1.96 SDS at 7 years and +1.30 SDS at 4 years of age. Skeletal surveys showed macrodactyly of the great toes and pseudo-epiphyses of the mid- and proximal phalanges. Sequencing identified a novel heterozygous variant c.1444_1449delATGCTG in exon 8 of NPR2, predicted to result in deletion of 2 amino acids Met482-Leu483 within the submembrane region of NPR-B. In proband's skin fibroblasts, basal cGMP levels and CNP-stimulated cGMP production were markedly increased compared with controls. Consistently, assays with transfected HEK-293 cells showed markedly augmented baseline and ligand-dependent activity of mutant NPR-B. CONCLUSIONS: We report the second activating variant within the intracellular submembrane region of NPR-B resulting in tall stature and macrodactyly. Our functional and modeling studies suggest that this domain plays a critical role in the baseline conformation and ligand-dependent structural rearrangement of NPR-B required for cGMP production
Case report : a novel deep intronic splice-altering variant in DMD as a cause of Becker muscular dystrophy
We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291–13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD
Clinical Characteristics of Pathogenic <i>ACAN </i>Variants and 3-Year Response to Growth Hormone Treatment:Real-World Data
Introduction: Heterozygous variants in the ACAN gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). Methods: The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous ACAN variant. Thirty-six subjects (23 boys, 13 girls) with ACAN deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. Results: We identified 25 different heterozygous ACAN variants in 36 subjects. Median (interquartile range) height SDS at start of GH was -2.6 SDS (-3.2 to -2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating ACAN variant had a shorter height SDS compared to subjects with a non-truncating variant (-2.8 SDS and -2.1 SDS, respectively, p = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9-1.4). In pubertal children, height SDS remained relatively stable. Conclusion: The phenotype of subjects with pathogenic heterozygous ACAN variants is highly variable, and genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with ACAN deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment.</p
Clinical Characteristics of Pathogenic <i>ACAN </i>Variants and 3-Year Response to Growth Hormone Treatment:Real-World Data
Introduction: Heterozygous variants in the ACAN gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). Methods: The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous ACAN variant. Thirty-six subjects (23 boys, 13 girls) with ACAN deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. Results: We identified 25 different heterozygous ACAN variants in 36 subjects. Median (interquartile range) height SDS at start of GH was -2.6 SDS (-3.2 to -2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating ACAN variant had a shorter height SDS compared to subjects with a non-truncating variant (-2.8 SDS and -2.1 SDS, respectively, p = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9-1.4). In pubertal children, height SDS remained relatively stable. Conclusion: The phenotype of subjects with pathogenic heterozygous ACAN variants is highly variable, and genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with ACAN deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment.</p
Phenotypic Features and Response to GH Treatment of Patients with a Molecular Defect of the IGF-1 Receptor
Context The phenotype and response to GH treatment of children with an IGF1R defect is insufficiently known. Objective To develop a clinical score for selecting children with short stature for genetic testing and evaluate the efficacy of treatment. Design and Setting Case series with an IGF1R defect identified in a university genetic laboratory. Patients and Interventions Of all patients with sufficient clinical data, 18 had (likely) pathogenic mutations (group 1) and 7 had 15q deletions including IGF1R (group 2); 19 patients were treated with GH. Main Outcome Measures Phenotype and response to GH treatment. Results In groups 1 and 2, mean (range) birth weight, length, and head circumference (HC) SD scores (SDSs) were -2.1 (-3.7 to -0.4), -2.7 (-5.0 to -1.0), and -1.6 (-3.0 to 0.0), respectively. At presentation, height, HC, and serum IGF-1 SDSs were -3.0 (-5.5 to -1.7), -2.5 (-4.2 to -0.5), and +1.2 (-1.3 to 3.2), respectively. Feeding problems were reported in 15 of 19 patients. A clinical score with 76% sensitivity is proposed. After 3 years of GH treatment [1.1 (0.2) mg/m 2 /d] height gain in groups 1 (n = 12) and 2 (n = 7) was 0.9 SDS and 1.3 SDS (at a mean IGF-1 of 3.5 SDS), less than reported for small for gestational age (1.8 SDS). Conclusion A clinical score encompassing birth weight and/or length, short stature, microcephaly, and IGF-1 is useful for selecting patients for IGF1R analysis. Feeding problems are common and the growth response to GH treatment is moderate