Integrating nutrition and genetic counseling: A case study approach to interprofessional learning.

Interprofessional collaboration is an increasingly important skillset for practicing healthcare professionals including genetic counselors and registered dietitian nutritionists. A multi-part interactive case study activity was created to develop interprofessional skills for graduate students within genetic counseling and medical nutrition training programs at an academic medical center. Feedback from learners who participated in this activity highlights its effect on their post-graduation clinical practice. Additionally, since the implementation of this activity, collaboration between students and faculty members of each program has occurred in other scholarly pursuits, fostering longstanding interprofessional relationships. Similar approaches to interprofessional education could be considered with other healthcare professions or at other institutions as another tool to strengthen practice upon graduation.

Telehealth genetic services during the COVID-19 Pandemic: Implementation and patient experiences across multiple specialties in Nebraska.

The COVID-19 pandemic has altered the delivery of genetics services. In response to the pandemic, our genetics department offered telehealth visits to all outpatients, regardless of their physical proximity to Omaha, Nebraska. Traditionally, our department did not offer telehealth visits to patient's homes or to patients who lived in close proximity to a genetics clinic. Therefore, we designed a survey to gain insight into the patient experience with remote genetic counseling appointments during the pandemic. Any patient referred to see a genetics provider in pediatrics, prenatal, adult, or cancer between March 16, 2020 and October 28, 2020 was eligible for the study. The survey included both quantitative and qualitative measures to assess patient demographics, patient experience, stressors during the COVID-19 pandemic, and anxiety and depression. We hypothesized that patients would report they received quality care by telehealth despite the presence of COVID-19-related stressors or anxiety/depression. From the 143 survey participants, 80% had their first telehealth appointment during the pandemic. The vast majority (96%) reported that they felt like they received quality care by telehealth. Additionally, more than 93% of participants strongly or somewhat agreed that their genetic providers were attentive to their emotional needs, medical needs, and privacy. Since March 2020, participants reported experiencing several COVID-19-related stressors including fear of illness (86%), feelings of isolation (45%), and safety concerns (33%). Relatively low levels of depressive and anxiety symptoms were recorded using the HADS questionnaire. Despite the prevalence of COVID-19 stressors, depression, and/or anxiety, our participants felt they received quality care via telehealth. In fact, 51% agree that they prefer to receive future genetics services virtually. These results suggest the value of telehealth as an alternative service delivery model, even for local patients, and should be offered for future appointments, beyond the COVID-19 pandemic.

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.

Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.

The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.

MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death.

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Chromosome 22q11.2 deletion syndrome in African-American patients: a diagnostic challenge.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with numerous and variable clinical manifestations including conotruncal heart abnormalities, palatal anomalies, hypoparathyroidism, immune deficiency, and cognitive deficits. The clinical suspicion of this syndrome is often heightened by the presence of characteristic facial features. A previous report highlighted the under-diagnosis of this condition in African Americans, thought to be related to a paucity of typical facial features. We ascertained the largest cohort (n = 50) of African-American individuals with 22q11DS reported thus far, across five genetics centers in the United States and report on their facial and other phenotypic features. About 3/4 of our cohort has at least one dysmorphic facial feature. Auricular abnormalities, especially small ears, are the most common dysmorphic facial feature followed by nasal and ocular abnormalities. Skeletal findings are seen in about 2/3 of our cohort, higher than the typical frequency reported in 22q11DS. Cardiac anomalies, developmental delay, and palatal abnormalities are seen at a lower frequency in our cohort. Thus, it is evident that the features traditionally associated with 22q11DS are difficult to recognize in African-American individuals with this syndrome, due to both altered frequencies of major anomalies and a non-classic facial appearance. Therefore, a high index of suspicion is needed to recognize 22q11DS in African-American individuals.

5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C.

Haploinsufficiency of RASA1, located on chromosome 5q14.3, has been identified as the etiology underlying the disorder capillary malformation-arteriovenous malformation (CM-AVM). Recently, haploinsufficiency of MEF2C, located 1.33 Mb distal to RASA1 on chromosome 5q14.3, has been implicated as the genetic etiology underlying a complex array of deficits including mental retardation, hypotonia, absent speech, seizures, and brain anomalies. Here we report a patient who is haploinsufficient in both RASA1 and MEF2C who presents with dermatologic and neurologic abnormalities that constitute a 5q14.3 neurocutaneous syndrome. This finding highlights the need to assess for CM-AVM in patients with neurologic features consistent with MEF2C haploinsufficiency, and vice versa.

Optic nerve enlargement in Krabbe disease: a pathophysiologic and clinical perspective.

Krabbe disease is an infantile-onset progressive leukodystrophy. The classic presentation includes excessive irritability, muscle hypertonicity, developmental delay, failure to thrive, peripheral neuropathy, seizures, and optic nerve atrophy. The authors report a rare case of optic nerve enlargement early in infantile Krabbe disease. Their case demonstrates proximal prechiasmatic enlargement of the nerves. They discuss the pathophysiological and clinical correlation of optic nerve enlargement in Krabbe disease and in other disorders. Although Krabbe disease does not feature in initial differential of optic nerve enlargement in children, its inclusion and early identification facilitate a timely diagnosis of this rapidly progressive fatal disease.

Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency.

Human FOXP2 deficiency has been identified as a cause of hereditary developmental verbal dyspraxia. Another member of the same gene family, FOXP1, has expression patterns that overlap with FOXP2 in some areas of the brain, and FOXP1 and FOXP2 have the ability to form heterodimers. These findings suggest the possibility that FOXP1 may also contribute to proper speech development. However, no such role of FOXP1 has been established to date. Recently, a child was reported who presented with a 3p13-14.1 deletion of four genes, including FOXP1, and a constellation of deficits that included speech delay. In this study, we report the case of a patient with a single deletion of FOXP1. This patient presented with speech and motor developmental delays, a Chiari I malformation, and epileptiform discharges. The nature of the speech deficit is different from the primary oromotor verbal dyspraxia found in patients with FOXP2 deficiency. The patient's developmental deficits may support a role for FOXP1 in the development of verbal and motor skills.