CTNNB1‐related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual ...defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1‐related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1‐related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.
An international group of clinicians working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and ...reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Additional discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we introduce the anatomy of the trunk and limbs and define and illustrate the terms that describe the major characteristics of these body regions.
Affirmation of children's understanding of information provided in genetic counseling encounters is crucial to obtaining children's informed consent/assent in pediatric genetic counseling encounters. ...It is also important for the proper management of a genetic condition. Currently, there is a relative scarcity of research on how understanding of complex genetic information by children is elicited in the process of pediatric genetic counseling. In this study, we apply theme‐oriented discourse analysis to examine 23 video/audio‐recorded genetic counseling encounters in Hong Kong. The encounters involve children aged between 3 and 17 years old who are suspected to have or diagnosed with Sudden Arrhythmic Death Syndrome (SADS). Specifically, we examine a range of communicative strategies that genetic professionals employ to elicit children's understanding of information in this genetic counseling setting. We also examine how children's epistemic status is negotiated between genetic professionals, parents, and children. The study reveals that genetic professionals typically use direct questioning (e.g., “do you understand?” or “do you have any questions?”). Less typical are examples where genetic professionals explore children's epistemic access and invite children to recall information after they deliver it. The study reveals two discourse strategies that genetic professionals and parents employ to justify a child's low epistemic status: (1) construction of “current ignorance” and “future competence” in children and (2) association with a child's character. In the examined counseling encounters, genetic professionals and parents tend to construct a low epistemic status in younger children and allocate the responsibility for understanding relevant information to the parents and the “future” competent children. The study highlights the impact of genetic professionals’ and parents’ assumptions on children's knowledge and comprehensibility at different ages, and the role that children themselves play in conforming or contesting these assumptions.
Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. ...It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31‐years‐old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long‐term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.
Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and ...RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi‐exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse‐shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007–0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype.
Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 ...families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and “major spliceosome-opathies” as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.
•Loss of spliceosomal components PPIL1 and PRP17 occurs in pontocerebellar hypoplasia•Modeling shows neural apoptosis and disrupted global RNA splicing integrity•PPIL1 and PRP17 form an enzyme-substrate pair within the active spliceosome•PPIL1 and PRP17 control splicing independent of enzyme activity
Chai et al. discover that loss of splicing factors PPIL1 and PRP17 leads to a neurodegenerative brain disease, and even though they are an enzyme-substrate pair, they function instead to scaffold the spliceosome.
Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum ...disorder. Although
is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients.
We performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR.
We identified ten pathogenic/likely pathogenic mutations in
(
= 4),
(
= 3),
(
= 1) and
(
= 2) in ten patients. An additional
mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic
mutation, making him harbour bi-allelic germline
mutations. Two patients harboured somatic
mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly.
We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder.
Mowat–Wilson syndrome (MWS) is characterized clinically by a distinctive facial gestalt, intellectual disability, microcephaly, epilepsy, and nonobligatory congenital malformations such as ...Hirschsprung disease, urogenital anomalies, congenital heart disease, eye malformations. This article summarized the clinical features and molecular findings of 15 Chinese MWS patients. The results revealed a higher incidence of congenital heart disease in Chinese MWS patients compared to that previously reported in Caucasian cohorts, while the incidence of Hirschsprung disease and genitourinary malformation appeared to be lower. This suggests possible ethnicity‐related modifying effects in the MWS phenotype.
Training in clinical genetics and genetic counseling in Asia Cutiongco‐de la Paz, Eva Maria; Chung, Brian Hon‐Yin; Faradz, Sultana M. H. ...
American journal of medical genetics. Part C, Seminars in medical genetics,
June 2019, 2019-06-00, 20190601, Letnik:
181, Številka:
2
Journal Article
The status of training in clinical genetics and genetic counseling in Asia is at diverse stages of development and maturity. Most of the training programs are in academic training centers where ...exposure to patients in the clinics or in the hospital is a major component. This setting provides trainees with knowledge and skills to be competent geneticists and genetic counselors in a variety of patient care interactions. Majority of the training programs combine clinical and research training which provide trainees a broad and integrated approach in the diagnosis and management of patients while providing opportunities for research discoveries that can be translated to better patient care. The background on how the training programs in clinical genetics and genetic counseling in Asia evolved to their current status are described. Each of these countries can learn from each other through sharing of best practices and resources.
Schuurs‐Hoeijmakers syndrome (SHS) is a rare syndrome involving a de novo variant in the PACS1 gene on chromosome 11q13. There are 36 individuals published in the literature so far, mostly diagnosed ...postnatally (34/36) after recognizing the typical facial features co‐occurring with developmental delay, intellectual disability, and multiple malformations. Herein, we present one prenatal and 15 postnatal cases with the recurrent heterozygous pathogenic variant NM_018026.3:c.607C>T p.(Arg203Trp) in the PACS1 gene detected by exome sequencing. These 16 cases were identified by mining Centogene and the Hong Kong clinical genetic service databases. Collectively, the 49 postnatally diagnosed individuals present with typical facial features and developmental delay, while the three prenatally diagnosed individuals present with multiple congenital anomalies. In the current study, the use of exome sequencing as an unbiased diagnostic tool aided the diagnosis of SHS (pre‐ and postnatally). The identification of additional cases with SHS add to the current understanding of the clinical phenotype associated with pathogenic PACS1 variants. Databases combining clinical and genetic information are helpful for the study of rare diseases.
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