Urea cycle disorders in critically Ill adults.

PURPOSE OF REVIEW: Urea cycle disorders (UCDs) cause elevations in ammonia which, when severe, cause irreversible neurologic injury. Most patients with UCDs are diagnosed as neonates, though mild UCDs can present later - even into adulthood - during windows of high physiologic stress, like critical illness. It is crucial for clinicians to understand when to screen for UCDs and appreciate how to manage these disorders in order to prevent devastating neurologic injury or death. RECENT FINDINGS: Hyperammonemia, particularly if severe, causes time- and concentration-dependent neurologic injury. Mild UCDs presenting in adulthood are increasingly recognized, so broader screening in adults is recommended. For patients with UCDs, a comprehensive, multitiered approach to management is needed to prevent progression and irreversible injury. Earlier exogenous clearance is increasingly recognized as an important complement to other therapies. SUMMARY: UCDs alter the core pathway for ammonia metabolism. Screening for mild UCDs in adults with unexplained neurologic symptoms can direct care and prevent deterioration. Management of UCDs emphasizes decreasing ongoing ammonia production, avoiding catabolism, and supporting endogenous and exogenous ammonia clearance. Core neuroprotective and supportive critical care supplements this focused therapy.

Implementation of a dedicated cascade testing clinic for patients at risk for hereditary cancer syndromes.

Cascade testing, the site-specific genetic testing of relatives within families with an inherited condition, is underutilized. Long wait times for appointments in specialty genetics clinics are a known barrier to genetic testing access. In our cancer genetics, New Patient Clinic (NPC), the long wait time for an appointment (on average 5 months for routine referrals), was identified by both providers and patients as a barrier to uptake of cascade testing. Timely testing of at-risk relatives is essential to maximize the benefits of cascade testing and reduce cancer morbidity and mortality. Our objective was to improve access via implementation of a different clinical model that designated appointments for patients seeking cascade testing. A secondary goal was to improve use of genetic counselor time. We implemented a dedicated Cascade Testing Clinic (CTC) with an expedited triaging and unique scheduling model to decrease patient wait time to appointment and optimize clinician time. We report on the process and outcomes here. Between October 2016 and February 2020, the average wait time between referral date and first scheduled appointment date was 46 days for the CTC compared to 144 days for the NPC (p < 0.0001). No-show/cancelation/rescheduling rate was 11.7% in the CTC compared to 29.7% in the NPC (p < 0.0001). Genetic counselors saw approximately twice as many patients per half-day clinic in the CTC compared to the NPC (p < 0.00001). Modifications to clinic staffing and appointment times were made based on provider feedback. Implementation of a dedicated clinic specifically for patients seeking cascade testing significantly shortened wait times for this population, reduced patient drop-off, and improved clinician efficiency. The relatively straightforward indications and generally uncomplicated medical histories made this an ideal population for expedited appointments.

Trainee perspectives of COVID-19 impact on medical genetics education.

PURPOSE: The SARS-CoV-2 pandemic abruptly altered medical education and clinical care. This work evaluates trainee perspectives of the impact of the pandemic on medical genetics education. METHODS: A Qualtrics survey was sent to physician trainees who rotated in genetics before or midpandemic. Questions assessed patient care, didactic education, and competency in multiple domains. Number of clinic visits completed by trainees were collated through review of documentation. RESULTS: Twenty-three rotating residents completed the surveys. Five of the pediatric residents completed the elective during the pandemic. All residents participated in virtual care during the pandemic, and rotating residents reported an improvement in self-assessed competency in multiple domains. Potential weak areas of education midpandemic included dysmorphology and genetic counseling. CONCLUSION: Residents on a genetics elective can gain crucial skills and knowledge even when the rotation is in a primarily virtual format. Supplemental dysmorphology and genetic counseling education may improve remote educational experiences. Further research across institutions may deepen understanding of the impact of the pandemic on education in genetics.

The introduction of clinical genetic testing in Ethiopia: Experiences and lessons learned.

Limited data are available on genetic testing laboratories in low- and middle-income countries including those in sub-Saharan Africa (SSA). To characterize the need for genetic testing in SSA we describe the experience of MRC-ET Advanced Laboratory, a genetic testing laboratory in Ethiopia. Test results were analyzed based on indication(s) for testing, referral category, and diagnostic yield. A total of 1311 tests were run using the full MRC-Holland catalogue of Multiplex-Ligation Probe Amplification assays. Of all samples, 77% were postnatal samples, 15% products of conception (POC), and 8% amniotic samples. Of postnatal samples, the most common testing categories were multiple congenital anomalies (32%), disorders of sex development (17%), and Obstetrics/Gynecology (16%). Forty-three percent of postnatal samples were diagnostic, 11% were variants of uncertain significance (VUS), and 46% were normal with Trisomy 21 the most common diagnosis. Of POC samples, 10% were diagnostic, 34% revealed VUSs, and 55% were normal with Trisomy 18 the most common diagnosis. Of amniotic samples 17.5% were diagnostic, 3% revealed VUSs, and 79% were normal with Trisomy 18 the most common diagnosis. There is increasing demand for genetic testing in Ethiopia. Diagnostic genetic testing in SSA deserves increased attention as testing platforms become more affordable.

Knowledge and attitudes about genetic counseling in patients at a major hospital in Addis Ababa, Ethiopia.

Previous work at St. Paul's Hospital Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia, demonstrated a need for genetic counseling (GC) services, with 4% of pediatric, neonatal intensive care, and prenatal patients identified as having indications for genetic evaluation (Quinonez et al, 2019). The aim of this study was to investigate SPHMMC patients' familiarity with, knowledge of, and attitudes toward GC services. Surveys were adapted from previous work in North America populations (Riesgraf et al, 2015 and Gemmell et al, 2017) and administered to 102 patients, and results were compared to North American populations using Student's t test. 30% of respondents reported at least some familiarity with GC, primarily via the media or healthcare providers. Patients had generally positive attitudes toward GC, reporting they would trust information provided by a genetic counselor and that GC is in line with their values. Knowledge of GC showed similar trends overall when compared to results from North American populations. Our work indicates limited exposure to GC in this population, but generally positive feelings toward GC. Patients' attitudes toward GC were comparable to rural North American populations surveyed using the same tool on most items; however, cultural differences including views on abortions and directiveness of healthcare providers could account for discrepancies and are important considerations when implementing genetic services globally.

The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.

Correction: The CHD4-related syndrome: a comprehensive investigation of the clinical spectrum, genotype-phenotype correlations, and molecular basis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

BACKGROUND: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice. CONCLUSIONS: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Introducing medical genetics services in Ethiopia using the MiGene Family History App.

PURPOSE: Almost all low-income countries and many middle-income countries lack the capacity to deliver medical genetics services. We developed the MiGene Family History App (MFHA), which assists doctors with family history collection and population-level epidemiologic analysis. The MFHA was studied at St. Paul's Hospital in Addis Ababa, Ethiopia. METHODS: A needs assessment was used to assess Ethiopian physicians' experience with genetics services. The MFHA then collected patient data over a 6-month period. RESULTS: The majority of doctors provide genetics services, with only 16% reporting their genetics knowledge is sufficient. A total of 1699 patients from the pediatric ward (n = 367), neonatal intensive care unit (NICU) (n = 477), and antenatal clinic (n = 855) were collected using the MFHA with a 4% incidence of a MFHA-screened condition present. The incidence was 11.7% in the pediatric ward, 3% in the NICU, and 0.5% in the antenatal clinic. Heart malformations (5.5% of patients) and trisomy 21 (4.4% of patients) were the most common conditions in the pediatric ward. CONCLUSION: Medical genetics services are needed in Ethiopia. As other countries increase their genetics capacity, the MFHA can provide fundamental genetics services and collect necessary epidemiologic data.

Patient preferences for prenatal testing and termination of pregnancy for congenital anomalies and genetic diseases in Ethiopia.

OBJECTIVE: As prenatal diagnostic services expand throughout low-income countries, an important consideration is the appropriateness of these services for patients. In these countries, services now include prenatal ultrasound and occasionally genetic testing. To assess patient interest, we surveyed pregnant patients at a hospital in Addis Ababa, Ethiopia, on their preferences for prenatal testing and termination of affected pregnancies for congenital anomalies and genetic diseases. METHOD: One hundred one pregnant patients were surveyed on their preferences for prenatal testing and termination of affected pregnancies using a survey covering various congenital anomalies and genetic diseases. RESULTS: Eighty-nine percent of patients reported interest in testing for all conditions. Three percent of patients were not interested in any testing. Over 60% of patients reported interest in termination for anencephaly, early infant death, severe intellectual disability, hemoglobinopathy, and amelia. Patients were more likely to express interest in prenatal testing and termination for conditions associated with a shortened lifespan. CONCLUSION: Ethiopian patients were interested in prenatal testing and termination of pregnancy for many conditions. Advancing prenatal diagnostic capacities is a potential strategy for addressing the incidence of congenital anomalies and genetic disease in Ethiopia. Importantly, there exist many factors and technological limitations to consider before implementation.

A Marfan syndrome-like phenotype caused by a neocentromeric supernumerary ring chromosome 15.

Small supernumerary marker chromosomes (sSMC) are abnormal chromosomes that cannot be characterized by standard banding cytogenetic techniques. A minority of sSMC contain a neocentromere, which is an ectopic centromere lacking the characteristic alpha-satellite DNA. The phenotypic manifestations of sSMC and neocentromeric sSMC are variable and range from severe intellectual disability and multiple congenital anomalies to a normal phenotype. Here we report a patient with a diagnosis of Marfan syndrome and infertility found to have an abnormal karyotype consisting of a chromosome 15 deletion and a ring-type sSMC likely stabilized by a neocentromere derived via a mechanism initially described by Barbara McClintock in 1938. Analysis of the sSMC identified that it contained the deleted chromosome 15 material and also one copy of FBN1, the gene responsible for Marfan syndrome. We propose that the patient's diagnosis arose from disruption of the FBN1 allele on the sSMC. To date, a total of 29 patients have been reported with an sSMC derived from a chromosomal deletion. We review these cases with a specific focus on the resultant phenotypes and note significant difference between this class of sSMC and other types of sSMC. Through this review we also identified a patient with a clinical diagnosis of neurofibromatosis type 1 who lacked a family history of the condition but was found to have a chromosome 17-derived sSMC that likely contained NF1 and caused the patient's disorder. We also review the genetic counseling implications and recommendations for a patient or family harboring an sSMC. © 2016 Wiley Periodicals, Inc.

The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re-evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family's clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that "the patient" can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient's daughter's pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient's husband's internet search of his wife's clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re-evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.

Human HOX gene disorders.

The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies.

9p partial monosomy and disorders of sex development: review and postulation of a pathogenetic mechanism.

Deletion of the distal segment of 9p causes a syndrome comprising trigonocephaly, minor anomalies, and intellectual disability. Patients with this condition also frequently present with genitourinary abnormalities including cryptorchidism, hypospadias, ambiguous genitalia, or 46,XY testicular dysgenesis. The region responsible for the gonadal dysgenesis has been localized to 9p24.3 with the likely responsible gene identified as DMRT1. Similar to patients with other molecular causes of 46,XY gonadal dysgenesis, patients with partial del 9p have an increased risk of gonadoblastoma. We present two patients with 46,XY gonadal dysgenesis due to partial 9p monosomy. Both patients were also diagnosed with gonadoblastoma following gonadectomy at an early age. Chromosomal microarray analyses refined the cytogenetic abnormalities and allowed potential genotype-phenotype relationships to be determined. We also review the literature as it pertains to partial 9p monosomy, genital abnormalities and gonadoblastoma and note that a large percentage of affected patients present with two copy number variations. We propose that a two-hit mechanism may be involved in the incomplete penetrance and variable expressivity of partial 9p monosomy and an abnormal genital phenotype. The significant percentage of gonadoblastoma in patients with 46,XY complete gonadal dysgenesis due to partial 9p monosomy also continues to support the necessity of gonadectomy in this patient population.

Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation.

Polyalanine repeat expansion diseases are hypothesized to result from unequal chromosomal recombination, yet mechanistic studies are lacking. We identified two de novo cases of hand-foot-genital syndrome (HFGS) associated with polyalanine expansions in HOXA13 that afforded rare opportunities to investigate the mechanism. The first patient with HFGS was heterozygous for a de novo nine codon polyalanine expansion. Haplotype investigation showed that the expansion arose on the maternally inherited chromosome but not through unequal crossing over between homologs, leaving unequal sister chromatid exchange during mitosis or meiosis or slipped mispairing as possible explanations. The asymptomatic father of the second patient with HFGS was mosaic for a six codon polyalanine expansion. Multiple tissue PCR and clonal analysis of paternal fibroblasts showed only expansion/WT and WT/WT clones, and haplotype data showed that two unaffected offspring inherited the same paternal allele without the expansion, supporting a postzygotic origin. Absence of the contracted allele in the mosaic father does not support sister chromatid exchange in the origin of the expansion. Mosaicism for HOXA13 polyalanine expansions may be associated with a normal phenotype, making examination of parental DNA essential in apparently de novo HFGS cases to predict accurate recurrence risks. We could not find an example in the literature where unequal sister chromatid exchange has been proven for any polyalanine expansion, suggesting that the principal mechanism for polyalanine expansions (and contractions) is slipped mispairing without repair or that the true frequency of unequal sister chromatid exchange involving these repeats is low.

Maternal intrachromosomal insertional translocation leads to recurrent 1q21.3q23.3 deletion in two siblings.

We identified a novel 6.33 Mb deletion of 1q21.3q23.3 (hg18; chr1: 153035245-159367106) in two siblings presenting with blepharophimosis, ptosis, microbrachycephaly, severe psychomotor, and intellectual disability. Additional common features include small corpus callosum, normal birth length and head circumference, postnatal growth restriction, low anterior hairline, upturned nose, bilateral preauricular pits, widely spaced teeth, gingival hypertrophy, left ventricular dilatation with decreased biventricular systolic function, delayed bone age, 5th finger clinodactyly, short 3rd digit, hyperconvex nails, obstructive and central sleep apnea, and bilateral heel contractures. Fluorescence in situ hybridization (FISH) performed in the mother of both children showed an apparently balanced, intrachromosomal insertional translocation of 1q21.3q23.3 to 1q42.12. The sibling recurrence likely arose by a maternal meiotic crossing over on the rearranged chromosome 1 between the deleted region and the insertion. We hypothesize that the decreased cardiac function and contractures may be related to LMNA haploinsufficiency. This case illustrates the importance of FISH when attempting to determine inheritance of a copy-number variation and emphasize the value of evaluating known haploinsufficiency phenotypes for genes in deleted regions.

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome.

BACKGROUND: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants. METHODS: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant. RESULTS: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05). CONCLUSIONS: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.

A 1-year and 4-month-old child with mucopolysaccharidoses type II: A clinical case report from Ethiopia.

Mucopolysaccharidoses (MPSs) are a class of lysosomal storage disorders resulting in progressive disease manifestations and are caused by pathogenic variants in genes coding for enzymes needed to degrade glycosaminoglycans. While most of the seven MPSs are autosomal recessive disorders, MPS II, also known as Hunter syndrome, is inherited in an X-linked recessive manner and is the most common MPS. Here, we report a 1-year and 4-month-old boy who presented with delayed developmental milestones, back deformity, and left scrotal swelling noticed by parents at one year of age. He has coarse facial appearance with macrocephaly, widened wrists, congenital dermal melanocytosis on his back, kyphotic deformity in the thoracolumbar area and left-sided inguinal hernia all consistent with a suspected MPS II diagnosis. The MPS II diagnosis was subsequently confirmed with genetic testing of the IDS gene. To our knowledge, this is the first case of MPS II reported from Ethiopia. This case shows the importance of early clinical recognition of genetic conditions and the utility of genetic testing for confirmation. The diagnosis provided important surveillance and natural history information for the patient's providers and family.