Background
SYNJ1 encodes Synaptojanin‐1, a dual‐function poly‐phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants ...cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy.
Methods
Proband‐only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant.
Results
We present an Afro‐Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242‐2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years.
Conclusions
We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1‐related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.
We present an individual with developmental and epileptic encephalopathy due to homozygosity for a novel SYNJ1 pathogenic c.242‐2A>G variant. The SYNJ1 protein functions to regulate synaptic vesicle recycling in neurons. Very few papers describing SYNJ1 variants are in the medical literature.
We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource‐limited islands in the West Indies. Due to geographic isolation, ...small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2–3 clinics per year on various islands in the Caribbean. We also organized a week‐long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow‐up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.
Prions are novel kinds of hereditary units, relying solely on proteins, that are infectious and inherited in a non-Mendelian fashion. To date, they are either based on autocatalytic modification of a ...3D conformation or on autocatalytic cleavage. Here, we provide further evidence that in the filamentous fungus Podospora anserina, a MAP kinase cascade is probably able to self-activate and generate C, a hereditary unit that bears many similarities to prions and triggers cell degeneration. We show that in addition to the MAPKKK gene, both the MAPKK and MAPK genes are necessary for the propagation of C, and that overexpression of MAPK as that of MAPKKK facilitates the appearance of C. We also show that a correlation exists between the presence of C and localization of the MAPK inside nuclei. These data emphasize the resemblance between prions and a self-positively regulated cascade in terms of their transmission. This thus further expands the concept of protein-base inheritance to regulatory networks that have the ability to self-activate.
Background
Individuals with various sized terminal duplications of chromosome 5p or terminal deletions of chromosome 18q have been described. These aberrations may cause congenital malformations and ...intellectual disability of varying severity.
Methods
Via an international collaborative effort, we obtained a cytogenetic diagnosis for a 5‐year‐old boy of Afro‐Caribbean ancestry who has global developmental delay, dysmorphology, hypotonia, feeding difficulties, bilateral club feet, and intellectual disability.
Results
Conventional G‐banded karyotyping showed additional chromatin of unknown origin on the long arm of chromosome 18. SNP microarray confirmed the loss of ~6.4 Mb from chromosome 18q: arrhg19 18q22.3‐q23(71,518,518‐77,943,115)x1. The source of the additional chromatin was determined from the microarray to be ~32 Mb from the short arm of chromosome 5 (arrhg19 5p13.3‐p15.33(51,045‐32,062,984)x3). The unbalanced translocation was verified by fluorescent in situ hybridization (FISH). Both parents are healthy and have normal karyotypes suggesting that this abnormality arose de novo in the proband, although gonadal mosaicism in a parent cannot be excluded.
Conclusion
The combination of clinical features in this individual is most likely due to the partial deletion of 18q and partial duplication of 5p, which to our knowledge has not been previously described.
We describe a 5‐year‐old boy who has global developmental delay, dysmorphology, and multiple congenital abnormalities. Karyotype showed additional chromatin on chromosome 18q. Microarray showed an approximate 32 Mb duplication of material from chromosome 5p (partial trisomy), and an approximate 6.2 Mb deletion from chromosome 18q (partial monosomy). FISH confirmed the unbalanced translocation.
Background
Grenada is a small, resource‐limited Caribbean country with a high incidence of sickle cell disease (SCD). Since little is known about the challenges facing individuals living with SCD in ...the West Indies, we sought to assess barriers to healthcare and the impact of SCD on quality of life in Grenada.
Methods
Both adults aged 18+ (n = 19) and caregivers of children aged 2–17 (n = 26) completed validated survey measures regarding barriers to care and quality of life, along with a genetics knowledge questionnaire. Caregivers also completed a caregiver burden scale. Survey scores were calculated, and responses were analyzed for an association between demographic variables.
Results
The Barriers to Care Questionnaire, in which lower scores indicate more barriers, revealed that both adults (mean = 69.9) and children (mean = 75.5) with SCD experienced reduced access to care. The Adult Sickle Cell Quality of Life Measurement Information System indicated increased depression and loneliness in adults, with the lowest scores in the Emotional subscale. However, the Pediatric Quality of Life Inventory answered by caregivers of children with SCD showed the lowest scores in the Physical Functioning subscale. Further analysis using the Caregiver Burden Scale‐Zarit Burden Interview revealed that 53.8% of caregivers of children with SCD indicated “little to no burden,” which may reflect a difference in cultural expectations of a caregiver between high‐income countries and Grenada. Finally, ~80% of respondents knew that SCD was a genetic condition; however, 61%–84% could not correctly indicate recurrence risks, demonstrating a need for additional education.
Conclusion
These data provide new insights regarding the experience of living with SCD in Grenada and support the need for further investigations into specific barriers to healthcare delivery, which could also improve education and well‐being for those affected by SCD in Grenada and in the broader Caribbean community.
Grenada is a small, resource‐limited Caribbean country with a high incidence of sickle cell disease (SCD). Despite the prevalence, little is known about the challenges facing individuals living with SCD. In this study, caregivers of children with SCD and adults with SCD reported a variety of barriers to care and reduced quality of life that highlight the need for improvements to infrastructure, including education, facilities, and personnel, to facilitate earlier diagnosis and improved lifelong therapeutic management for individuals with SCD.
Response to Hamosh et al Biesecker, Leslie G; Adam, Margaret P; Alkuraya, Fowzan S ...
American journal of human genetics,
09/2021, Volume:
108, Issue:
9
Journal Article
It is a matter of course that in high‐income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a ...definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low‐ and middle‐income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource‐limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource‐limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.
BackgroundDystonia is a relatively common feature of spinocerebellar ataxia 3 (SCA3). Childhood onset of SCA3 is rare and typically associated with either relatively large, or homozygous, CAG repeat ...expansions. Case reportWe describe a 10-year-old girl with SCA3, who presented with tongue dystonia in addition to limb dystonia and gait ataxia due to a heterozygous expansion of 84 repeats in ATXN3. DiscussionDiagnosis of the SCAs can be challenging, and even more so in children. Tongue dystonia has not previously been documented in SCA3.
BackgroundAccess to medical care in many regions is limited by socioeconomic status, at both the individual and the community level. This report describes the diagnostic process of a family residing ...on an underserved Caribbean island where routine neurological care is typically addressed by general practitioners, and genetic diagnosis is not available through regular medical channels. The diagnosis and management of neurodegenerative disorders is especially challenging in this setting. Case ReportWe diagnosed a family with spinocerebellar ataxia type 3 (SCA3) in an underdeveloped nation with limited access to genetic medicine and no full-time neurologist. DiscussionMolecular diagnosis of the SCAs can be challenging, even in developed countries. In the Caribbean, genetic testing is generally only available at a small number of academic centers. Diagnosis in this family was ultimately made by utilizing an international, pro bono, research-based collaborative process. Although access to appropriate resources, such as speech, physical, and occupational therapies, is limited on this island because of economic and geographical factors, the provision of a diagnosis appeared to be ultimately beneficial for this family. Identification of affected families highlights the need for access to genetic diagnosis in all communities, and can help direct resources where needed.
Background
Cornelia de Lange syndrome (CdLS) comprises a recognizable pattern of multiple congenital anomalies caused by variants of the DNA cohesion complex. Affected individuals may display a wide ...range of phenotypic severity, even within the same family.
Methods
Exome sequencing and confirmatory Sanger sequencing showed the same previously described p.Arg629Ter NIPBL variant in two half‐brothers affected with CdLS. Clinical evaluations were obtained in a pro bono genetics clinic.
Results
One brother had relatively mild proportionate limb shortening; the other had complete bilateral hypogenesis of the upper arm with absence of lower arm structures, terminal transverse defects, and no digit remnants. His complex lower limb presentation included long bone deficiency and a deviated left foot. The mother had intellectual disability and microcephaly but lacked facial features diagnostic of the CdLS.
Conclusion
We describe a collaboration between a pediatrics team from a resource‐limited nation and USA‐based medical geneticists. Reports describing individuals of West Indian ancestry are rarely found in the medical literature. Here, we present a family of Afro‐Caribbean ancestry with CdLS presenting with phenotypic variability, including unusual lower limb abnormalities. The observation of this novel family adds to our knowledge of the phenotypic and molecular aspects of CdLS.
We found the same pathogenic NIPBL variant in two half‐brothers who are of Afro‐Caribbean ancestry. One of the brothers has a novel lower limb presentation.
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