Familial Segregation Research Articles

Novel homozygous frameshift variant in the ATCAY gene in an Iranian patient with Cayman cerebellar ataxia; expanding the neuroimaging and clinical features: a case report

BackgroundPathogenic variants in the ATCAY gene are associated with a rare autosomal recessive disorder called Cayman cerebellar ataxia. Affected individuals display psychomotor retardation, cerebellar dysfunction, nystagmus, intention tremor, ataxic gait and dysarthric in some cases.Case presentationWhole exome sequencing was performed for a 21-month-old girl suffering from developmental delay specifically in motor and language aspects, hypotonia, nystagmus, pes planus and strabismus. The detected variant in the patient was confirmed by family segregation analysis by Sanger sequencing in both of her parents. Previously three homozygous variants in the ATCAY gene (missense, splice site and frameshift deletion) have been reported in patients with Cayman cerebellar ataxia. Here we report the fourth homozygous variant and the second homozygous frameshift deletion in this gene to be associated with autosomal recessive Cayman cerebellar ataxia.ConclusionThe identification of this novel homozygous frameshift deletion in the ATCAY gene expands our understanding of the genetic landscape underlying Cayman cerebellar ataxia. Furthermore, the occurrence of this variant in Iran, in addition to Pakistan, signifies the importance of considering genotypic and phenotypic factors beyond ethnicity when studying this disorder. These findings contribute to the ongoing efforts to unravel the molecular basis of Cayman cerebellar ataxia and improve diagnostic approaches and potential therapeutic interventions.

Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.

Approximately 10% of primary hyperparathyroidism cases are hereditary, due to germline mutations in certain genes. Although clinically relevant, a systematized genetic diagnosis is missing due to a lack of firm evidence regarding individuals to test and which genes to evaluate. A customized gene panel (AIP, AP2S1, CASR, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, GCM2, GNA11, MEN1, PTH, RET, and TRPV6) was performed in 40 patients from the Mediterranean area with suspected familial hyperparathyroidism (≤45 years of age, family history, high-risk histology, associated tumour, multiglandular disease, or recurrent hyperparathyroidism). We aimed to determine the prevalence of germline variants in these patients, to clinically characterize the probands and their relatives, and to compare disease severity in carriers versus those with a negative genetic test. Germline variants were observed in 9/40 patients (22.5%): 2 previously unknown pathogenic/likely pathogenic variants of CDKN1B (related to MEN4), 1 novel variant of uncertain significance of CDKN2C, 4 variants of CASR (3 pathogenic/likely pathogenic variants and 1 variant of uncertain significance), and 2 novel variants of uncertain significance of TRPV6. Familial segregation studies allowed diagnosis and early treatment of PHPT in first-degree relatives of probands. The observed prevalence of germline variants in the Mediterranean cohort under study was remarkable and slightly higher than that seen in other populations. Genetic screening for suspected familial hyperparathyroidism allows the early diagnosis and treatment of PHPT and other related comorbidities. We recommend genetic testing for patients with primary hyperparathyroidism who present with high-risk features.

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy

PurposeTo summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges. MethodsData acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology. In case of single-exon deletion, sequencing of the specific exon was performed to rule out underlying single-nucleotide variant. ResultsOf overall 85,737 DMD tests, 82 clinically significant findings were noted (0.095%, or 1:1,046 women). In addition, 80 findings with uncertain clinical significance were detected (0.093%, or 1:1072), as well as 373 cases (0.4%, or 1:230) of single-exon deletions subsequently identified as false positives because of underlying single-nucleotide variant, mostly variants in exon 8 in North African Jewish population, and in exon 48 in Arab Muslim population. ConclusionInterpretation of population-based DMD carrier screening is complex, occasionally requiring additional genetic testing methods and ethical considerations. Multicenter data registry, including ethnic origin and familial segregation in selected cases, is crucial for optimal definition of the results during genetic counseling and informed decisions regarding prenatal testing.

A novel likely pathogenic CLCN5 variant in Dent’s disease

BackgroundThe majority of cases of Dent’s disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity.Case presentationA 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an unrelated paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant.ConclusionsThe identification of this novel variant in four individuals with features of Dent’s disease, has led to the re-classification of the variant to one of likely pathogenicity.As a result, our patients and any future patients with the same variant can be offered a likely diagnosis, without the need for kidney biopsy, and their family members can be offered genetic screening.

A very rare disease of lymphatic malformation 6: five new patients and review of the literatur

Objective: Lymphatic Malformation 6 (MIM no:616843) is characterized by generalized edema, bilateral pleural effusions, ascites and non-immune hydrops fetalis. PIEZO1 gene has been associated with the LMPHM6 disorder. Here, we aimed to evaluate five patients from two different families, with various clinical presentations of generalized lymphatic dysplasia.
 Materials and Methods: Between January 2015 and January 2021, 5 cases with were evaluated with a pre-diagnosis of congenital lymphatic malformation. Whole exome sequencing was performed on the probands, and family segregation analysis was performed by Sanger sequencing.
 Results: We identified a novel compound heterozygous PIEZO1 gene: NM_001142864.4: c.4030_4032delGAG (E1344del)/ c.5455_5456delAA (K1819Efs*46) variants in the first family and a novel homozygous PIEZO1 gene: c.5876A>G (D1959G) variant in the second family.
 Conclusion: This study, which presents the clinical features and variations of five patients with long-term follow-up, contributed to the phenotypic and mutation spectrum of Lymphatic Malformation 6. The novel compound heterozygous E1344del/K1819Efs*46 variation leads to a premature stop codon that caused a shorter protein product. It was thought that two compound nonsense variations might be associated with the poor prognosis of family 1. Also, the second novel c.5876A>G (D1959G) biallelic homozygous mutation was thought to be associated with impaired PIEZO1 by causing loss of function. This study was the first LMPHM6 report from the Turkish population.
 Keywords: Neurofibromatosis type 1, Next generation DNA sequencing, NF1 gene, novel variants

The spectrum of hereditary neuromuscular disorders in the Pakistani population.

Hereditary neuromuscular disorders (NMDs) are a broad group of clinically heterogeneous disorders with varying inheritance patterns, that are associated with over 500 implicated genes. In the context of a highly consanguineous Pakistani population, we expect that autosomal recessive NMDs may have a higher prevalence compared with patients of European descent. This is the first study to offer a detailed description of the spectrum of genes causing hereditary NMDs in the Pakistani population using NGS testing. To study the clinical and genetic profiles of patients presenting for evaluation of a hereditary neuromuscular disorder. This is a retrospective chart review of patients seen in the Neuromuscular Disorders Clinic and referred to the Genetics Clinic with a suspected hereditary neuromuscular disorder, between 2016 and 2020 at the Aga Khan University Hospital, Karachi and Mukhtiar A. Sheikh Hospital, Multan, Pakistan. The genetic testing for these patients included NGS-based single gene sequencing, NGS-based multi-gene panel and whole exome sequencing. In a total of 112 patients studied, 35 (31.3%) were female. The mean age of onset in all patients was 14.6 years (SD ±12.1 years), with the average age at presentation to the clinic of 22.4 years (SD ±14.10 years). Forty-seven (41.9%) patients had a positive genetic test result, 53 (47.3%) had one or more variants of uncertain significance (VUS), and 12 (10.7%) had a negative result. Upon further genotype-phenotype correlation and family segregation analysis, the diagnostic yield improved, with 59 (52.7%) patients reaching a diagnosis of a hereditary NMD. We also report probable founder variants in COL6A2, FKTN, GNE, and SGCB, previously reported in populations that have possible shared ancestry with the Pakistani population. Our findings reemphasizes that the rate of VUSs can be reduced by clinical correlation and family segregation studies.

O-303 Contribution of targeted sequencing for genetic diagnosis of premature ovarian insufficiency in clinical practice

Abstract Study question What is the diagnostic yield of custom designed gene panel for patients with premature ovarian insufficiency (POI)? Summary answer The diagnostic yield of our POI gene panel (POIGP) is 7.3% What is known already POI is a specific female syndrome with a high clinical and genetic heterogeneity. It is characterized by a premature exhaustion of the ovarian function and infertility and affects approximately 1% of women. POI can be related to genetic factors which include chromosomal abnormalities, FMR1 premutation and rare variants in numerous genes. The advent of high throughput sequencing methods has led to the identification of an increasing number of variants implicated in the development of POI over the last decades. However, POI etiologies still remain undetermined in the majority of cases. Study design, size, duration An observational analytic cohort study of 150 patients presenting idiopathic POI (normal karyotype, absence of FMR1 premutation, absence of adrenal and/or ovarian antibodies) recruited prospectively at three Belgian academic and university hospitals between 2016 and 2021. Participants/materials, setting, methods Patients were included if they experienced POI, as defined by ESHRE guidelines on POI (2016). POI genes included in the panel were selected from PubMed using different key words mainly premature ovarian insufficiency, gonadal dysgenesis, hypergonadotropic hypogonadism, ovarian failure and genetics. The panel included 156 genes, variants were filtered based on allele frequency (≤1%) in latest available population databases and classified according to ACMG/AMP (American College of Medical Genetics/Association for Molecular Pathology) guidelines 2015. Main results and the role of chance Our analysis revealed a potential causative variant for 11 patients in the following genes: MEIOB, BMP4, CFTR, FANCA, FSHR, FANCG, MLH1, MRPS22 and STARD9. This means that the diagnostic yield of our POI gene panel (POIGP) is 7.3%. Patients were mainly Caucasian (63%), North African (17%) and sub-Saharan African (13%). They presented primary amenorrhea in 14.7% of cases. Consanguinity and/or a family history of POI or early menopause in 28% of cases. Mean patient’s age (years) at POI diagnosis was 28.9± 8.5 (mean ± SD). The overall mean coverage was 229X, and more than 95% of the target exome was represented with more than 30-fold coverage. Limitations, reasons for caution The present study was limited to monogenic etiologies of POI, potential oligogenic causes have not been searched. Functional studies and/or family segregation were not performed for the identified variants. Wider implications of the findings Our findings show the importance of targeted next generation sequencing in clinical practice and highlight the limit of our current genetic knowledge in the field of POI. A regular update of genes included in POIGP will improve its diagnostic yield. Trial registration number P2016/196/CCB B406201628264

RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature.

RNA sequencing (RNA-seq) is a complementary diagnostic tool to exome sequencing (ES), only recently clinically available to undiagnosed patients post-ES, that provides functional information on variants of unknown significance (VUS) by evaluating its effect on RNA transcription. ES became clinically available in the early 2010s and promised an agnostic platform for patients with a neurological disease, especially for those who believed to have a genetic etiology. However, the massive data generated by ES pose challenges in variant interpretation, especially for rare missense, synonymous, and deep intronic variants that may have a splicing effect. Without functional study and/or family segregation analysis, these rare variants would be likely interpreted as VUS which is difficult for clinicians to use in clinical care. Clinicians are able to assess the VUS for phenotypic overlap, but this additional information alone is usually not enough to re-classify a variant. Here, we report a case of a 14-month-old male who presented to clinic with a history of seizures, nystagmus, cerebral palsy, oral aversion, global developmental delay, and poor weight gain requiring gastric tube placement. ES revealed a previously unreported homozygous missense VUS, c.7406A > G p.(Asn2469Ser), in VPS13D. This variant has not been previously reported in genome aggregation database (gnomAD), ClinVar, or in any peer-reviewed published literature. By RNA-seq, we demonstrated that this variant mainly impacts splicing and results in a frameshift and early termination. It is expected to generate either a truncated protein, p.(Val2468fs*19), or no protein from this transcript due to nonsense-mediated mRNA decay leading to VPS13D deficiency. To our knowledge, this is the first case utilizing RNA-seq to further functionally characterize a homozygous novel missense VUS in VPS13D and confirm its impact on splicing. This confirmed pathogenicity gave the diagnosis of VPS13D movement disorder to this patient. Therefore, clinicians should consider utilizing RNA-seq to clarify VUS by evaluating its effect on RNA transcription.

Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review.

Familial hypobetalipoproteinemia (FHBL) is an autosomal semi-dominant disorder usually caused by variants in the APOB gene that frequently interferes with protein length. Clinical manifestations include malabsorption, non-alcoholic fatty liver disease, low levels of lipid-soluble vitamins, and neurological, endocrine, and hematological dysfunction. Genomic DNA was isolated from the blood samples of the pediatric patient with hypocholesterolemia and his parents and brother. Next-generation sequencing (NGS) was performed, and an expanded dyslipidemia panel was employed for genetic analysis. In addition, a systematic review of the literature on FHBL heterozygous patients was performed. Genetic investigation revealed the presence of a heterozygous variant in the APOB (NM_000384.3) gene c.6624dup[=], which changes the open reading frame and leads to early termination of translation into the p.Leu2209IlefsTer5 protein (NP_000375.3). The identified variant was not previously reported. Familial segregation analysis confirmed the variant in the mother of the subject, who also has a low level of low-density lipoprotein and non-alcoholic fatty liver disease. We have introduced therapy that includes limiting fats in the diet and adding lipid-soluble vitamins E, A, K, and D and calcium carbonate. We reported 35 individuals with APOB gene variations linked to FHBL in the systematic review. We have identified a novel pathogenic variant in the APOB gene causing FHBL in pediatric patients with hypocholesterolemia and fatty liver disease. This case illustrates the importance of genetic testing for dyslipidemias in patients with significant decreases in plasma cholesterol as we can avoid damaging neurological and ophthalmological effects by sufficient vitamin supplementation and regular follow-ups.

Success and Pitfalls of Genetic Testing in Undiagnosed Diseases: Whole Exome Sequencing and Beyond.

Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in MEIS2, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in NIPBL causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy.

The implementation of NGS methods into clinical practice allowed researchers effectively to establish the molecular cause of a disorder in cases of a genetically heterogeneous pathology. In cases of several potentially causative variants, we need additional analysis that can help in choosing a proper causative variant. In the current study, we described a family case of hereditary motor and sensory neuropathy (HMSN) type 1 (Charcot-Marie-Tooth disease). DNA analysis revealed two variants in the SH3TC2 gene (c.279G>A and c.1177+5G>A), as well as a previously described variant c.449-9C>T in the MPZ gene, in a heterozygous state. This family segregation study was incomplete because of the proband's father's unavailability. To evaluate the variants' pathogenicity, minigene splicing assay was carried out. This study showed no effect of the MPZ variant on splicing, but the c.1177+5G>A variant in the SH3TC2 gene leads to the retention of 122 nucleotides from intron 10 in the RNA sequence, causing a frameshift and an occurrence of a premature stop codon (NP_078853.2:p.Ala393GlyfsTer2).

Whole genome sequencing in the 100,000 Genomes project identifies a RYR2 variant associating with dilated cardiomyopathy and sudden unexpected death in the young

Abstract Funding Acknowledgements Type of funding sources: None. Background Previous studies have shown genetic testing in sudden unexpected death in the young (SUDY) cases identify a pathogenic variant in 13-27% of cases. This diagnostic yield increased up to 39% when genetic testing was combined with family evaluation. The 100,000 Genomes Project was launched to investigate the role of whole genome sequencing (WGS) as a diagnostic tool for cancers and rare diseases in a national health care system. Young sudden death victims with no finding on postmortem testing were enrolled to the SUDY cohort. Purpose We aimed to analyse WGS data in the SUDY cohort of 100,000 Genomes Project with panel analysis and trio studies in order to examine the yield of WGS in this population. Methods Sudden death victims, aged 40 or younger, without pre-existing condition that would explain the event and with no diagnosis established on postmortem examination were enrolled between 2017 and 2019 at different Genomic Medicine Centres (GMCs) across the UK. Parents were recruited in all paediatric cases. DNA sequencing was performed by Illumina. The platform's automated pipeline was used for variant calling. Panel based and hypothesis free approaches were used for data analysis. Variant analysis was performed with focus on variants with combined annotation-dependent depletion (CADD) score >15 and American College of Medical Genetics and Genomics (ACMG) classification of pathogenic (P), likely pathogenic (LP), or variant of unknown significance (VUS). Results A total of 15 participants, including 6 trios, were included in the study. Participants had a median age of 18 [IQR 1-29.5] and two thirds were male. Following assessment of all protein coding and intronic variants identified, only the missense variant RYR2:c.10046C>T (p.Ser3349Leu) was thought to be suitable for investigation for upgrade to likely pathogenic, giving a diagnostic yield of 6.67% for WGS in SUDY cases. This variant was detected in a 24-year-old sudden death victim. Family evaluation led to the diagnosis of dilated cardiomyopathy (DCM) in four family members and segregation testing confirmed affected family members harboured the variant. Further investigation in 100,000 Genomes Project, laboratory data, and our inherited cardiac conditions database as well as previous publications, identified additional cases of this variant in association with DCM and sudden cardiac death (see table and figure). Conclusion WGS with targeted gene analysis can be an effective diagnostic tool for SUDY. The study’s findings show the importance of large population databases and collaboration in the research community, allowing reclassification of a RYR2 VUS as a LP variant, the strongest genetic data so far to associate a missense variant with familial DCM and the risk for SCD. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project.

ConsCal: A tool to aid medical genetics professionals in consanguineous populations.

Consanguineous populations have a higher frequency of autosomal recessive diseases when compared to the rest of the world. This frequency is high enough that families in these populations may even have multiple autosomal recessive diseases. The recurrence risk calculation for the various combinations becomes increasingly more difficult as more recessive diseases are encountered in a family. Another challenge in these populations is investigating the pathogenicity of a variant by considering its segregation with the phenotype. Consanguinity causes the appearance of many homozygous variants due to the identity by descent phenomenon. As the number of these variants increases, so does the percentage of novel variants that need to be classified using segregation. Furthermore, the complexity of calculating the segregation power increases with the level of inbreeding, and in the case of consanguineous families, their pedigrees tend to be very complex. With the aim of addressing these two challenges using a mathematical algorithm, ConsCal, a tool made to specifically cater to medical genetics professionals working with consanguineous populations, was developed. The user-friendly tool contains two primary functions. It simplifies recurrence risk calculations for any combination of autosomal recessive diseases and analyzes familial segregation data to assign a numerical value to the segregation power of a given variant to aid in its classification. As the use of genomics becomes more widespread, this tool can help address the growing need in calculating recurrence risk and segregation power in consanguineous populations.

Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8.

Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

SMARCE1-related meningiomas: A clear example of cancer predisposing syndrome

We report the case of a 16-year-old girl presenting with spinal clear-cell multiple meningiomas (CCMs). In view of this presentation, we sequenced a bioinformatic panel of genes associated with susceptibility to meningioma, identifying a germline heterozygous variant in SMARCE1. Somatic DNA investigations in the CCM demonstrated the deletion of the wild-type allele (loss of heterozygosity, LOH), supporting the causative role of this variant. Family segregation study detected the SMARCE1 variant in the asymptomatic father and in the asymptomatic sister who, nevertheless, presents 2 spinal lesions. Germline heterozygous loss-of-function (LoF) variants in SMARCE1, encoding a protein of the chromatin-remodeling complex SWI/SNF, have been described in few familial cases of susceptibility to meningioma, in particular the CCM subtype. Our case confirms the role of NGS in investigating predisposing genes for meningiomas (multiple or recurrent), with specific regard to SMARCE1 in case of pediatric CCM. In addition to the age of onset, the presence of familial clustering or the coexistence of multiple synchronous meningiomas also supports the role of a genetic predisposition that deserves a molecular assessment. Additionally, given the incomplete penetrance, it is of great importance to follow a specific screening or follow-up program for symptomatic and asymptomatic carriers of pathogenic variants in SMARCE1.

The genetic counselor: recognizing their critical role in neurology clinics in the era of genomic medicine (P12-4.001)

<h3>Objective:</h3> To describe the critical role of the clinical genetic counselor in the neurology setting and their impact on patient care. <h3>Background:</h3> Genetic testing is increasingly utilized in the diagnosis of neurodegenerative disorders. This is particularly relevant as the field moves towards neurogenetic intervention. Determining who should be genetically tested, which tests should be performed, which labs are most appropriate and how to secure insurance coverage for patients with neurological conditions remains a challenge. Reviewing the complexity of testing options and potential impact of the results on patients and family members is also time-consuming and can be a barrier to care when physicians are required to fill this role unassisted by clinical professionals with targeted genetic expertise. Genetic counselors are healthcare professionals with specialized training in medical genetics and psychosocial counseling who can solve this challenge in clinical care. <h3>Design/Methods:</h3> Here we describe the role and impact of genetic counselor in the Massachusetts General Hospital Ataxia Center as a case in point. <h3>Results:</h3> The genetic counselor’s primarily roles are in pretest and posttest counseling. Pretest counseling includes comprehensive genetic evaluations and determining appropriate genetic testing pathways for individuals with suspected hereditary ataxic disorders. They review test benefits, limitations, and risks, impacts on patients and family members, and facilitate prior authorizations for insurance approval and test orders. Posttest counseling involves disclosure of sensitive results in the context of the patient’s medical and family history, and incudes psychosocial support. Follow up includes connecting patients to resources and support groups, arranging family segregation studies in case of uncertain results, and cascade testing for at risk relatives. <h3>Conclusions:</h3> The genetic counselor’s knowledge and counseling skills help improve patient care, optimize physician time, focus the testing strategy, and reduce costs. Genetic counselors are integral members of the multidisciplinary neurology team in the era of genomic medicine. <b>Disclosure:</b> Ms. Chen has nothing to disclose. Dr. Schmahmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medavante. Dr. Schmahmann has stock in Cadent. The institution of Dr. Schmahmann has received research support from National Ataxia Foundation. The institution of Dr. Schmahmann has received research support from Biohaven. Dr. Schmahmann has received intellectual property interests from a discovery or technology relating to health care. Dr. Schmahmann has received publishing royalties from a publication relating to health care. Dr. Schmahmann has received publishing royalties from a publication relating to health care. Dr. Schmahmann has received publishing royalties from a publication relating to health care.

A novel compound heterozygous mutation of the CLCN7 gene is associated with autosomal recessive osteopetrosis.

Osteopetrosis is a genetic condition of the skeleton characterized by increased bone density caused by osteoclast formation and function defects. Osteopetrosis is inherited in the form of autosomal dominant and autosomal recessive manner. We report autosomal recessive osteopetrosis (ARO; OMIM 611490) in a Chinese case with a history of scarce leukocytosis, vision and hearing loss, frequent seizures, and severe intellectual and motor disability. Whole-exome sequencing (WES) followed by Sanger sequencing revealed novel compound heterozygous mutations in the chloride channel 7 (CLCN7) gene [c.982-1G > C and c.1208G > A (p. Arg403Gln)] in the affected individual, and subsequent familial segregation showed that each parent had transmitted a mutation. Our results confirmed that mutations in the CLCN7 gene caused ARO in a Chinese family. Additionally, our study expanded the clinical and allelic spectrum of the CLCN7 gene and enhanced the applications of WES technology in determining the etiology of prenatal diagnoses in fetuses with ultrasound anomalies.

Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension

BackgroundEarly-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger...

Hyper‐IgE syndrome presenting with early life craniosynostosis in monozygotic twin sisters

<scp>Hyper‐IgE</scp> syndrome presenting with early life craniosynostosis in monozygotic twin sisters

The Severity of Congenital Hypothyroidism with Gland-in-situ Predicts Molecular Yield by Targeted NGS.

Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. TSH at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.