Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited ...in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence.
A transversely isotropic structural model for wood, based on a polytope strength criterion, is proposed and deployed in the analysis of solid wood columna-capreoli A-trusses reproducing the geometry ...and connection details of those currently erected in the Aula Magna of the Monastery San Lorenzo ad Septimum in Aversa. The predictivity of the polytope strength criterion is assessed verifying its capability of identifying the closest crisis mode against experimental evidence from a simple flexural test, with minimal wood sacrifice. The model is employed in parametric optimization analyses to infer a design provision for the columna-capreoli connection which appears to be in reasonable agreement with the rule of the art empirically inferable from the observation of many samples of open-node King Post A-trusses belonging to the architectural heritage in Campania of historical and artistic value. A final discussion examines a perspective of extending these optimization analyses to the sustainability of the built environment.
•Design of traditional wood carpentry connections is discussed for sustainability.•A transversely isotropic strength-deformability model for wood is proposed.•The model is benchmarked.•Frame and membrane analyses of Vitruvian wood A trusses are presented.•Results are critically discussed in a perspective of sustainability.
CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic ...variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.
Interstitial deletions involving 6q chromosomal region are rare. Less than 30 patients have been described to date, and fewer have been characterized by high-resolution techniques, such as ...chromosomal microarray. Deletions involving 6q21q22.1 region are associated with an extremely wide and heterogeneous clinical spectrum, thus genotype-phenotype correlation based on the size of the rearranged region and on the involved genes is complex, even among individuals with overlapping deletions. Here we describe the phenotypic and molecular characterization of a new 6q interstitial deletion in a girl with developmental delay, intellectual disability, cerebellar vermis hypoplasia, facial peculiar characteristics, ataxia and ocular abnormalities. Microarray analysis of the proposita revealed a 7.9 Mb interstitial
deletion at 6q21q22.1 chromosomal region, which spanned from nucleotides 108,337,770 to 116,279,453 (GRCh38/hg38). The present case, alongside with a systematic review of the literature, provides further evidence that could aid to the definition of the Smallest Region of Overlap and of the genomic traits that are associated with particular phenotypes, focusing on neurological findings and especially on cerebellar anomalies.
Distal chromosome 16 duplication syndrome (also known as 16q partial trisomy) is a very rare genetic disorder recently described in few clinical reports. 16q trisomy is generally associated with a ...multisystemic phenotype including intrauterine growth restriction (IUGR), brain and cardiac defects, intellectual disability (ID) and an increased risk of both prenatal and postnatal lethality. Smaller copy number variants (CNV) within the 16q region create partial trisomies, which occur less frequently than full trisomy 16q.
We present the clinical case of a 12-years-old male with a 16q22.3q24.1 de novo heterozygous duplication whose phenotype was characterized by ID, facial dysmorphisms, stature and weight overgrowth. To date, only five other cases of this syndrome have been reported in scientific literature, and none of them comprised overgrowth.
Our case report highlights the great heterogeneity in clinical manifestations and provides new evidence for better defining the phenotypic picture for smaller 16q distal CNVs, suggesting unusual features.
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.
Recessive hereditary methemoglobinemia (RHM) due to NADH-cytochrome b5 reductase deficiency is a rare disease caused by pathogenic variants in
. Unlike type I, in RHM type II (RHM2), the enzymatic ...defect affects erythrocytes and all body tissues, thus resulting in cyanosis and neurological impairment. Although the first description of RHM2 dates back to the mid-1950s, detailed clinical and neuroimaging information are available for only a few patients. Here, we describe a new patient with RHM2 that harbors an unreported homozygous 31 Kb deletion involving part of
, and showing a peculiar neuroimaging pattern resembling a ponto-cerebellar hypoplasia-like condition. A careful review of the available literature was performed with the aim of better delineating neurological and neuroimaging as well as the genotypic spectra of this extremely rare disease.
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.
Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function ...variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95-97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies. Here, we report two unrelated patients presenting with two different inversions that disrupt the NF1 coding sequence, resulting in an NF1 phenotype. In one subject, the inversion was associated with microdeletions spanning a few NF1 exons at both breakpoints, while in the other the rearrangement did not cause exon loss, thus testing negative by MLPA assay. Considering the high proportion of repeated regions within the NF1 sequence, we propose that intragenic structural rearrangements should be considered as possible pathogenic mechanisms in patients fulfilling the NIH diagnostic criteria of NF1 but lacking of molecular confirmation and in patients with NF1 intragenic microdeletions.
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