Sotos syndrome is one of the most common overgrowth diseases and it predisposes patients to cancer, generally in childhood. The prevalence of this genetic disorder is 1:10,000⁻1:50,000, and it is ...characterized by wide allelic heterogeneity, with more than 100 different known mutations in the nuclear receptor-binding SET domain containing protein 1 (
) gene. Most of these alterations are deletions and common micro-deletions with haploinsufficiency. Singular variants are missense mutations. The present study reports a case of a 4-year-old boy with specific clinical features of Sotos syndrome and a particular complex skin hamartoma on the right femoral side, in addition to other minor findings, such as a "café-au-lait" spot on the right hemithorax and syndactyly of the second and third right toes.
gene analysis identified a de novo missense mutation, "c.5867T>A+="; "p.Leu1956Gln+=", that was not previously described in the literature. This mutation was localized to the functional domain of the gene and was likely the cause of Sotos syndrome in our patient. We also compared aspects of our patient's condition with the clinical features of tuberous sclerosis (TSC), which is an autosomal neurocutaneous syndrome caused by mutations in the
genes. These genes control cell growth and cell survival. This disorder is characterized by hamartomas in multiple organ systems, several coetaneous abnormalities, epilepsy, and increased risk of several types of tumors.
The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. ...The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.
Background
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-related disorder (OMIM #613735) is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment and non-specific dysmorphic features. ...To date, fewer than thirty patients affected by this disorder have been described.
Methods
Our study included three children with
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haploinsufficiency recruited from three medical genetics centers. Clinical presentations were recorded on a standardized case report form.
Results
All patients presented a variable degree of intellectual disability. None of the individuals in our cohort had urinary tract malformations. Three novel mutations, c.344G>A, c.261T>G, and c.887_888del are reported here.
Conclusion
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haploinsufficiency can be suspected through careful observation of specific dysmorphisms, including macrocephaly and craniofacial abnormalities. Instrumental tests such as MRI and renal ultrasound provide further diagnostic clues, while genetic testing can confirm the diagnosis.
Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems ...likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including
, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735). Our patient also has a deleted
of the
gene family of transcription factors, which plays an important role in neural crest cell growth and differentiation. As the murine
model shows craniofacial anomalies and abnormal common carotid artery morphology, it can be hypothesised that
is involved in the pathogenesis of the craniofacial and vascular defects observed in our patient. In support of our assumption, we found in the literature another patient with a syndromic form of MA who had a deletion involving another
gene (
). In addition to describing the clinical history of our patient, we have reviewed all of the available literature concerning other patients with a 1p32p31 deletion, including cases from the Decipher database, and we have also reviewed the genetic disorders associated with MA, which is a useful guide for the diagnosis of syndromic form of MA.
Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild ...mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 arrhg199q22.32(98,049,611_98,049,636)x3,9q22.33 (99,301,483_99,301,508)x3, involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.
In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal ...dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-β binding protein 3 (
) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic
variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous
splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in
are involved in its pathogenesis.
Heterozygous mutations in the
gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of ...Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of
pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance. Here, we describe a novel missense variant (c.1044 G>T, p.Arg118Met) in a Moroccan boy with a disproportionately short stature and without any radiological traits or bone deformities and in his mother, who had a disproportionately short stature and a Madelung deformity. This variant has not been reported to date in the updated
allelic variant or Human Gene Mutation Databases nor is it listed as a polymorphism in the ExAC browser, dbSNP, or 1000G. This mutation was predicted to be deleterious by three different bioinformatics tools since it modifies an amino acid in a highly conserved DNA-binding domain of the SHOX protein. Based on this evidence, the patient was treated with recombinant human growth hormone.
Abstract
Context
Familial isolated hypoparathyroidism (FIH) is a genetically heterogeneous disorder due to mutations of the calcium-sensing receptor (CASR), glial cells missing-2 (GCM2), guanine ...nucleotide binding protein α11 (GNA11), or parathyroid hormone (PTH) genes. Thus far, only four cases with homozygous and two cases with heterozygous mutations in the PTH gene have been reported.
Objective
To clinically describe an FIH family and identify and characterize the causal gene mutation.
Design
Genomic DNA of the family members was subjected to CASR, GCM2, GNA11, and PTH gene mutational analysis. Functional assays were performed on the variant identified.
Participants
Six subjects of a three-generation FIH family with three affected individuals having severe hypocalcemia and inappropriately low serum PTH.
Results
No mutations were detected in the CASR, GCM2, and GNA11 genes. A heterozygous variant that segregated with the disease was identified in PTH gene exon 2 (c.41T>A; p.M14K). This missense variant, in the hydrophobic core of the signal sequence, was predicted in silico to impair cleavage of preproPTH to proPTH. Functional assays in HEK293 cells demonstrated much greater retention intracellularly but impaired secretion into the medium of the M14K mutant relative to wild type. The addition of the pharmacological chaperone, 4-phenylbutyric acid, led to a reduction of cellular retention and increased accumulation in the cell medium of the M14K mutant.
Conclusions
We report a heterozygous PTH mutation in an FIH family and demonstrate accumulation of the mutant intracellularly and its impaired secretion. An accurate genetic diagnosis in such hypoparathyroid patients is critical for appropriate treatment and genetic counseling.
We report on a heterozygous PTH mutation in an FIH family and demonstrate accumulation of the mutant intracellularly and its impaired secretion.
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