A second hotspot for pathogenic exon-skipping variants in CDC45.

Biallelic pathogenic variants in CDC45 are associated with Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), which also includes short stature and absent/hypoplastic patellae. Identified variants act through a hypomorphic loss of function mechanism, to reduce CDC45 activity and impact DNA replication initiation. In addition to missense and premature termination variants, several pathogenic synonymous variants have been identified, most of which cause increased exon skipping of exon 4, which encodes an essential part of the RecJ-orthologue's DHH domain.

Pain Frequency and Health Care Utilization Patterns in Women with Sickle Cell Disease Experiencing Menstruation-Associated Pain Crises.

Pain crises in sickle cell disease (SCD) lead to high rates of health care utilization. Historically, women have reported higher pain burdens than men, with recent studies showing a temporal association between pain crisis and menstruation. However, health care utilization patterns of SCD women with menstruation-associated pain crises have not been reported.

Prospective identification of variables as outcomes for treatment (PIVOT): study protocol for a randomised, placebo-controlled trial of hydroxyurea for Ghanaian children and adults with haemoglobin SC disease.

Background: Haemoglobin SC (HbSC) is a common form of sickle cell disease (SCD), especially among individuals of West African ancestry. Persons with HbSC disease suffer from the same clinical complications and reduced quality of life that affect those with sickle cell anaemia (HbSS/Sβ). Retrospective anecdotal data suggest short-term safety and benefits of hydroxyurea for treating HbSC, yet rigorous prospective data are lacking regarding optimal dosing, clinical and laboratory effects, long-term safety and benefits, and appropriate endpoints to monitor.

Cervical precancer screening with HPV DNA testing and mobile colposcopy in women with sickle cell disease in Accra, Ghana.

Background: Worldwide, about 20-25 million people are affected by sickle cell disease (SCD), with 60% of patients living in sub-Saharan Africa. Despite recent therapeutic advancements resulting in improved life expectancy among SCD patients, the prevalence of high-risk human papillomavirus (hr-HPV) and cervical lesions have not been studied in women with SCD. We determined the prevalence of hr-HPV and cervical lesions among women with SCD and recommended strategies for reducing cervical cancer incidence in this cohort.

Periostin as a blood biomarker of muscle cell fibrosis, cardiomyopathy and disease severity in myotonic dystrophy type 1.

Background And Purpose: Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy and is caused by an repeat expansion [r(CUG)] located in the 3' untranslated region of the DMPK gene. Symptoms include skeletal and cardiac muscle dysfunction and fibrosis. In DM1, there is a lack of established biomarkers in routine clinical practice.

Most adults with severe HbSC disease are not treated with hydroxyurea.

Sickle cell hemoglobin SC (HbSC) disease is the second most frequent sickle cell disease (SCD) genotype after sickle cell anemia (HbSS). Globally, ∼55 000 newborns with HbSC are delivered annually, with the highest HbC gene frequency in West Africa. In Ghana, 40% of adults visiting the Ghana Institute of Clinical Genetics SCD clinic have HbSC.

A Homozygous PPP1R21 Splice Variant Associated with Severe Developmental Delay, Absence of Speech, and Muscle Weakness Leads to Activated Proteasome Function.

PPP1R21 acts as a co-factor for protein phosphatase 1 (PP1), an important serine/threonine phosphatase known to be essential for cell division, control of glycogen metabolism, protein synthesis, and muscle contractility. Bi-allelic pathogenic variants in PPP1R21 were linked to a neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) with pediatric onset. Functional studies unraveled impaired vesicular transport as being part of PPP1R21-related pathomechanism.

Chronic Eosinophilic Leukemia Presenting as Cardiac Failure.

Chronic eosinophilic leukemia (CEL) is a rare chronic myeloproliferative disorder characterized by sustained eosinophilia. Although the incidence of CEL is uncertain, it can be clinically devastating as it has a propensity to affect several important organ systems. This is of particular significance in Sub-Saharan Africa where helminthic infections are a more prevalent cause of eosinophilia.

Acute pain episodes, acute chest syndrome, and pulmonary thromboembolism in pregnancy.

Pregnancy in women with sickle cell disease (SCD) is a life-threatening condition. In both high- and low-income countries, there is an 11-fold increased risk of maternal death and a 4-fold increased risk of perinatal death. We highlight the epidemiology of SCD-specific and obstetric complications commonly seen during pregnancy in SCD and propose definitions for acute pain and acute chest syndrome (ACS) episodes during pregnancy.

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare germline missense variants in ; one identical variant was found in five individuals and another variant in two individuals.

A case-control and seven-year longitudinal neurocognitive study of adults with sickle cell disease in Ghana.

Ageing in sickle cell disease (SCD) is associated with a myriad of end-organ complications, including cerebrovascular damage and cognitive impairment (CI). Although CI is very common in SCD, little is known about cognitive functioning and how it changes with age. This study examines cognitive patterns of 63 adults with SCD and 60 non-SCD, age- and education-matched controls in Ghana.

Preanalytical Considerations and Outpatient Versus Inpatient Tests of Plasma Metanephrines to Diagnose Pheochromocytoma.

Context: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives.

Objective: We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines.

Polygenic risk scores indicate extreme ages at onset of breast cancer in female BRCA1/2 pathogenic variant carriers.

Background: Clinical management of women carrying a germline pathogenic variant (PV) in the BRCA1/2 genes demands for accurate age-dependent estimators of breast cancer (BC) risks, which were found to be affected by a variety of intrinsic and extrinsic factors. Here we assess the contribution of polygenic risk scores (PRSs) to the occurrence of extreme phenotypes with respect to age at onset, namely, primary BC diagnosis before the age of 35 years (early diagnosis, ED) and cancer-free survival until the age of 60 years (late/no diagnosis, LD) in female BRCA1/2 PV carriers.

Methods: Overall, estrogen receptor (ER)-positive, and ER-negative BC PRSs as developed by Kuchenbaecker et al.

Proteomic and morphological insights and clinical presentation of two young patients with novel mutations of BVES (POPDC1).

Popeye domain containing protein 1 (POPDC1) is a highly conserved transmembrane protein essential for striated muscle function and homeostasis. Pathogenic variants in the gene encoding POPDC1 (BVES, Blood vessel epicardial substance) are causative for limb-girdle muscular dystrophy (LGMDR25), associated with cardiac arrhythmia. We report on four affected children (age 7-19 years) from two consanguineous families with two novel pathogenic variants in BVES c.

Transition Preparation and Satisfaction of Care Among Adolescents and Young Adults With Sickle Cell Disease at the Ghana Institute of Clinical Genetics.

Expanding services in Ghana for people with sickle cell disease is expected to increase childhood survival and need for transition to adult care. Little is known about patient transition experiences in sub-Saharan Africa. We sought to understand those experiences of adolescents and young adults at an adult sickle cell clinic in Accra, Ghana.

PIGN encephalopathy: Characterizing the epileptology.

Objective: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy.

Methods: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment.

Pain Burden in the CASiRe International Cohort of Sickle Cell Patients: United States and Ghana.

Objectives: Sickle Cell Disease (SCD) is a genetic blood disorder affecting over 1 million people globally. The aim of this analysis is to explore the pain burden of patients with SCD in two countries: the United States and Ghana.

Methods: The Consortium for the Advancement of Sickle Cell Research (CASiRe) was created to better understand the clinical severity of patients with SCD worldwide.

Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.

The synthesis of cytochrome c oxidase 2 (SCO ) gene encodes for a mitochondrial located metallochaperone essential for the synthesis of the cytochrome c oxidase (COX) subunit 2. Recessive mutations in SCO have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency and in only four cases with axonal neuropathy. Here, we identified a homozygous pathogenic variant (c.

Global geographic differences in healthcare utilization for sickle cell disease pain crises in the CASiRe cohort.

Background: Sickle cell disease (SCD) is characterized by frequent, unpredictable pain episodes and other vaso-occlusive crises (VOCs) leading to significant healthcare utilization. VOC frequency is often an endpoint in clinical trials investigating novel therapies for this devastating disease.

Procedure: The Consortium for the Advancement of Sickle Cell Research (CASiRe) is an international collaboration investigating clinical severity in SCD using a validated questionnaire and medical chart review standardized across four countries (United States, United Kingdom, Italy and Ghana).