NRAS associated RASopathy and embryonal rhabdomyosarcoma Garren, Benjamin; Stephan, Mark; Hogue, Jacob S.
American journal of medical genetics. Part A,
January 2020, 2020-01-00, 20200101, Letnik:
182, Številka:
1
Journal Article
Recenzirano
RASopathies are a group of phenotypically overlapping disorders that arise from dysregulation of the RAS/MAPK pathway. These disorders include Noonan syndrome, Costello syndrome, cardiofaciocutaneous ...syndrome, and neurofibromatosis‐Type 1. While somatic mutations in the three human Ras genes (KRAS, HRAS, and NRAS) are a common finding in a variety of cancers, germline mutations in each of the these genes cause developmental RASopathy phenotypes with mutations in specific genes typically correlating with specific phenotypes. We present the case of a germline heterozygous NRAS mutation producing a severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi in addition to more typical manifestations of Noonan syndrome. Additionally, the specific p.G12R NRAS mutation in this case is a common somatic mutation in cancer cells, and analysis of previously reported NRAS‐RASopathy cases suggests that mutations at traditionally oncogenic codons are associated with elevated cancer risk not present with mutations at other sites.
Although parents are typically the most appropriate decision-makers for their children, there are limits to this authority. Medical providers may be ethically obligated to seek state intervention ...against a parental decision if the parent places a child at significant and imminent risk of serious harm. When parents make medical decisions for their children, they assess both the projected benefits and risks of their choices for their family. These assessments are impacted by uncertainty, which is a common feature of neonatal intensive care. The relative presence or absence of uncertainty may impact perceptions of parental decisions and a medical provider’s decision to seek state intervention to overrule parents. In this article, we propose a model integrating prognostic uncertainty into pediatric decision-making that may aid providers in such assessments. We will demonstrate how to apply this model to 3 neonatal cases and propose that the presence of greater uncertainty ought to permit parents greater latitude to incorporate family values into their decision-making even if these decisions are contradictory to the recommendations of the medical team.
Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations of the human foregut. The etiology remains incompletely understood with genetic causes identified in a ...small minority of affected patients. We present the case of a newborn with type C EA/TEF along with proximal symphalangism found to have a de novo NOG nonsense mutation. Patients with chromosome 17q deletions including the NOG gene have previously been reported to have EA/TEF but mutations in the gene have not been identified in patients with this malformation. This case provides evidence that haploinsufficiency for NOG may be the cause for EA/TEF in the 17q deletion syndrome and suggests that the clinical spectrum of NOG‐related symphalangism spectrum disorders may include EA/TEF.
NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different
...NAA10
missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited
NAA10
variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different
NAA10
missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.
ABSTRACT
Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core‐rod myopathy, congenital fiber‐type disproportion, distal ...arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal‐dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non‐hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head‐to‐tail binding.
We present mutation update and genotype‐phenotype correlations for novel (16) and previously reported (31) mutations of the TPM2 and TPM3 genes causing nemaline myopathy, cap myopathy, core‐rod myopathy, congenital fibre‐type disproportion, distal arthrogryposes and Escobar syndrome. Included are 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Six mutations cause increased Ca2+ sensitivity resulting in hypercontractile phenotypes. Our in silico predictions show that most mutations affect tropomyosin‐actin association or tropomyosin head‐to‐tail binding.
Recently, de novo heterozygous loss-of-function mutations in
beta
-
catenin
(
CTNNB1
) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited ...speech and (progressive) spasticity, and functional consequences of
CTNNB1
deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function
CTNNB1
mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically −2 to −4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating
CTNNB1
mutations and thereby clinically delineate this new
CTNNB1
haploinsufficiency syndrome.
Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. Mutations in the NIPBL gene ...predominate; however, mutations in other cohesin complex genes have also been implicated, particularly in atypical and mild CdLS cases. Missense mutations and whole gene deletions in RAD21 have been identified in children with growth retardation, minor skeletal anomalies and facial features that overlap findings in individuals with CdLS. We report the first intragenic deletion and frameshift mutations identified in RAD21 in two patients presenting with atypical CdLS. One patient had an in-frame deletion of exon 13, while the second patient had a c.592_593dup frameshift mutation. The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first patient being milder than the second. The in-frame deletion mutation was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems.
This study expands the spectrum of RAD21 mutations and emphasizes the clinical utility of performing RAD21 mutation analysis in patients presenting with atypical forms of CdLS. Moreover, the variability of clinical presentation within families and low penetrance of mutations as well as the significance of performing molecular genetic testing in mildly affected patients are discussed.
•Identification of novel mutations in RAD21 associated with atypical CdLS•First report of a RAD21 familial case•Variable clinical presentation associated with defects of the RAD21 gene
Congenital lumbar hernia–A feature of diabetic embryopathy? Stevens, Cathy A.; Hogue, Jacob S.; Hopkin, Robert J. ...
American journal of medical genetics. Part A,
November 2018, 2018-11-00, 20181101, Letnik:
176, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Congenital lumbar hernia is a rare anomaly consisting of protrusion of abdominal organs or extraperitoneal tissue through a defect in the lateral abdominal wall. The majority of affected patients ...have additional anomalies in a pattern described as the lumbocostovertebral syndrome. We report four patients born to mothers with poorly controlled diabetes with congenital lumbar hernia. All patients exhibited features of lumbocostovertebral syndrome with lumbar hernia, multiple vertebral segmentation anomalies in the lower thoracic and/or upper lumbar spine, rib anomalies, and unilateral renal agenesis. Additional anomalies present in the patients included preaxial hallucal polydactyly, abnormal situs, and sacral dysgenesis, anomalies known to be associated with diabetic embryopathy. At least 11 other patients have been previously reported with the lumbocostovertebral syndrome in the setting of maternal diabetes. We suggest that congenital lumbar hernia and the lumbocostovertebral syndrome are related to diabetic embryopathy.
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