Genetic Counseling Of Families Research Articles

NR3C2 microdeletions-an underrecognized cause of pseudohypoaldosteronism type 1A: a case report and literature review.

Pseudohypoaldosteronism type 1A (PHA1A) is caused by haploinsufficiency of the mineralocorticoid receptor (MR). Heterozygous small insertions/deletions, transitions, and/or transversions within NR3C2 comprise the majority (85%-90%) of pathogenic copy number variants. Structural chromosomal abnormalities, contiguous gene deletion syndromes, and microdeletions are infrequent. We describe a neonate with PHA1A due to a novel NR3C2 microdeletion involving exons 1-2. Literature review identified 39 individuals with PHA1A due to NR3C2 microdeletions. Transmission modality, variant description(s), testing method(s), exon(s) deleted, and affected functional domain(s) were characterized. In total, 40 individuals with NR3C2 microdeletions were described: 19 involved contiguous exons encoding a single MR domain; 21 involved contiguous exons encoding multiple MR domains. Transmission modality frequency was familial (65%), de novo (20%), or unknown (15%). Sequencing (Sanger or short-read next-generation) failed to detect microdeletions in 100% of tested individuals (n=38). All were detected using deletion/duplication testing modalities. In 2 individuals, only microarray-based testing was performed; microdeletions were detected in both cases. Initial testing for PHA1A should rely on sequencing to detect the most common genetic alterations. Deletion/duplication analysis should be performed when initial testing is nondiagnostic. Most NR3C2 microdeletions are parentally transmitted, thus highlighting the importance of familial genetic testing and counseling.

Clinical and Molecular Characteristics of Neuronal Ceroid Lipofuscinosis in Saudi Arabia

BackgroundNeuronal ceroid lipofuscinoses (NCLs) represent a heterogeneous group of inherited metabolic lysosomal disorders characterized by neurodegeneration. This study sought to describe the clinical and molecular characteristics of NCLs in Saudi Arabia and determine the most common types in that population. MethodsA retrospective review of electronic medical records was conducted for 63 patients with NCL (55 families) from six tertiary and referral centers in Saudi Arabia between 2008 and 2022. Clinical, radiological, and neurophysiological data as well as genetic diagnoses were reviewed. ResultsCLN6 was the predominant type, accounting for 45% of cases in 25 families. The most common initial symptoms were speech delay (53%), cognitive decline (50%) and/or gait abnormalities (48%), and seizure (40%). Behavioral symptomatology was observed in 20%, whereas visual impairment was less frequently (9.3%) encountered. Diffuse cerebral and cerebellar atrophy was the predominant finding on brain magnetic resonance imaging. Electroencephalography generally revealed background slowing in all patients with generalized epileptiform discharges in 60%. The most common genotype detected was the p.Ser265del variant found in 36% (20 of 55 families). The most rapidly progressive subtypes were CLN2 and CLN6. Two patients with each died at age five years. The earliest age at which a patient was nonambulatory was two years in a patient with CLN14. ConclusionsThis is the largest molecularly confirmed NCL cohort study from Saudi Arabia. Characterizing the natural history of specific NLC types can increase understanding of the underlying pathophysiology and distinctive genotype-phenotype characteristics, facilitating early diagnosis and treatment initiation as well as genetic counseling for families.

Prevalence of variant of unknown significance (VUS) in men with prostate cancer who serve as a benchmark for enhanced screening and for personalized therapy.

342 Background: Pathogenic variants (PVs) in DNA repair genes (DRG), such as in BRCA1, BRCA2, ATM, CHEK2, etc., have implications for prostate cancer (PCa) family genetic counselling, testing and risk stratification in men. However, understanding how to counsel patients with variants of unknown significance (VUS) is an unmet clinical need. On the other hand, there is the necessity to cautiously interpret VUS findings and to bolster VUS evaluations with additional evidence for pathogenicity. In this study, we aim to investigate the prevalence of germline VUS in men with PCa and their association with outcomes after robot-assisted radical prostatectomy (RARP). Methods: This is a nested cohort case study from an ongoing PCa screening, set to identify and screen men in the Italian population with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro project IG 2020 ID 25027). Cases for the current analysis were selected by “Adam's rib strategy” searching for germline DRG variant in men with a diagnosis of high-risk PCa who were scheduled for RARP. After informed consent was signed, a blood sample was obtained. A previously validated multigene panel test was used to assess the presence of germline variants. PVs and VUS were classified according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus criteria and International Agency for Research on Cancer guidelines. The primary endpoint was to describe the prevalence of VUS and the secondary to correlate VUS with pathological outcomes after RARP. Results: A total of 118 men with diagnosis of PCa who underwent RP were enrolled. The mean age at diagnosis of PCa was 65.9 (±6.42) years; pathological grade was ISUP 1-2 in 58.0% patients and 3-5 in 42.0%. Of the 76 men evaluated, 18 (23.7%) had a VUS and 1 (1.32%) a pathogenic germline variant in BRCA1 and PALB2. Among those with VUS younger men at diagnosis were more likely to carry a VUS than older at diagnosis mean (age 64 ± 6.41 vs. 66 ± 7.20 years). Additionally, 33.3% vs 16.2 % were carrier of VUS and N+ and required adjuvant androgen deprivation therapy. No difference between ISUP at final pathology and positive margin rate were found. Conclusions: Our findings showed a high prevalence of VUS germline mutations in PCa patients undergoing RARP. These mutations seem to be associated with worse pathological outcomes. Limitations includes short follow-up and absence of non-Caucasian patients.

Nephrotic Syndrome in a Child With NPHS2 Mutation.

Steroid resistant nephrotic syndrome (SRNS) accounts for 30% of all cases of nephrotic syndrome (NS) in children and frequently leads to end stage kidney disease (ESKD). About 30% of children with SRNS demonstrate causative mutations in podocyte- associated genes. Early identification of genetic forms of SRNS is critical to avoid potentially harmful immunosuppressive therapy. A 2-year-old male patient with NS and no family history of renal disease did not respond to 4-week steroid treatment. Kidney biopsy demonstrated mesangial proliferative glomerulopathy with basement membrane dysmorphism. Tacrolimus and Lisinopril were added to therapy pending results of genetic testing. Kidney Gene panel showed a NPHS2 c.413G>A (p.Arg138Gln) homozygous pathogenic variant. This missense variant is considered a common pathogenic founder mutation in European populations. A diagnosis of autosomal-recessive form of nonsyndromic SRNS due to NPHS2 causative variant was made. Immunosuppresive therapy was stopped, Lizinopril dose was increased and weekly infusions of Albumin/furosemide were initiated to manage edema. This case demonstrates that early genetic testing in children with SRNS avoids prolonged potentially harmful immunosuppressive therapy, allows for timely genetic family counseling, and allows earlier consideration for future living related donor kidney transplantation.

Novel compound heterozygous mutations of the NPC1 gene associated with Niemann-pick disease type C: a case report and review of the literature

BackgroundNiemann-Pick Disease type C is a fatal autosomal recessive lipid storage disorder caused by NPC1 or NPC2 gene mutations and characterized by progressive, disabling neurological deterioration and hepatosplenomegaly. Herein, we identified a novel compound heterozygous mutations of the NPC1 gene in a Chinese pedigree.Case presentationThis paper describes an 11-year-old boy with aggravated walking instability and slurring of speech who presented as Niemann-Pick Disease type C. He had the maternally inherited c.3452 C > T (p. Ala1151Val) mutation and the paternally inherited c.3557G > A (p. Arg1186His) mutation using next-generation sequencing. The c.3452 C > T (p. Ala1151Val) mutation has not previously been reported.ConclusionsThis study predicted that the c.3452 C > T (p. Ala1151Val) mutation is pathogenic. This data enriches the NPC1 gene variation spectrum and provides a basis for familial genetic counseling and prenatal diagnosis.

P-42 A delayed diagnosis of MEN1 syndrome

Abstract Introduction Multiple endocrine neoplasia 1 (MEN 1) is a rare autosomal dominantly inherited syndrome that results from mutations in the MEN1 gene. It is characterized by multiple tumors of endocrine glands and some other tissues. Early diagnosis is crucial for optimal management. Here we present a patient with delayed diagnosis and preventable metastatic disease. Clinical Case A 46-year-old male patient who was referred from gastroenterology clinic to our outpatient clinic following distal pancreatectomy. The postoperative pathology was reported as a well-differentiated neuroendocrine tumor (NET) with 3 focuses (60 mm, 9 mm and 2.5 mm in size). Six months ago, he underwent to Magnetic Resonance Imagination (MRI) of the abdomen because of abdominal pain and 17 kg weight loss in a year, that revealed a 69×67 mm cystic lesion in the tail of the pancreas (Figure 1A). Laboratory and physical examinations were in accordance with a nonfunctioning lesion (Table 1). The findings of the Gallium-68 DOTATATE PET/CT suggested residual and metastatic disease during follow-up (At the level of the pancreatic corpus, increased uptake was detected in two lesion sites adjacent to liver segment 3 and in various nodular lesion areas, the largest of which was approximately 20 mm in diameter, adjacent to the duodenum and pancreas (Figure 1B and 1D). No increased uptake was observed in the pancreas and these lesions in preoperative FDG/PET (Figure is not shown). The patient was consultated by oncology clinic and 177-Lutetium-DOTATATE and octreotide treatments were started. Parathyroidectomy and total thyroidectomy 7 years ago was noted in the patient's medical history. Persisting hypercalcemia and elevated PTH were also remarkable in laboratory testing (Table 2). The patient didn't apply to endocrinology clinic after parathyroidectomy and hypercalcemia had been overlooked for 7 years. Further investigation revealed a nonfunctioning 4 mm diameter pituitary lesion (Figure 1C). So the diagnosis of multiple endocrine neoplasia type 1 was suspected. Genetic test detected a c.784-2A>G spice site variant in MEN1 gene in heterozygous form. The patient denied a family history for MEN 1 but he reported that his father died at the age of 40 and his uncle at the age of 39 due to an illness of unknown origin, and two sons of the same uncle were followed up for parathyroid disease. Family screening and genetic counseling were recommended. Surgery of the remaining parathyroid glands and implantation in the forearm and thymectomy were planned. Conclusion MEN syndromes are rare and hypercalcemia is generally the initial presentation. Persistence of hypercalcemia following parathyroidectomy should be warning, and the possibility of MEN -1 syndrome should also be kept in mind even in the lack of family history. As in the presented case, diagnosis may be delayed due to late appearance of symptoms of other components, especially nonfunctional pancreaticoduodenal tumors.Figure 1.MRI and Ga-68 PET/CT images of the patientA: A 69×67 mm cystic lesion in the tail of the pancreas B: Increased Gallium-68 DOTATATE uptake at the level of the pancreatic corpus adjacent to liver segment 3 (SUVmax: 67.90) C: A nonfunctioning 4 mm diameter lesion in the right half of the pituitary D: Increased uptake of Gallium-68 DOTATATE in nodular lesions adjacent to the duodenum and pancreas (SUVmax: 31.09) Table 1.Laboratory results of the patientACTH: Adrenocorticotropic hormone, FSH: follicle stimulating hormone, LH: luteinizing hormone, IGF-1: Insülin-like growth factor, TSH: Thyroid stimulating hormone, 1 mg DST: dexamethasone suppression test Table 2.Calcium and PTH levels of the patient before parathyroidectomy and following parathyroidectomy*Before parathyroidectomy ** Following parathyroidectomy PTH: Parathyroid hormone

Angelman syndrome: A genetic challenge for physical and learning disabilities

Angelman syndrome (AS) was first reported in 1965 by Dr. Harry Angelman. It is a condition of neurodevelopment characterized by, a lack of speech, distinctive behavior, seizure, intellectual capacity, and cheerful disposition. The cause of AS is a lack of production by maternal imprinted genes (UBE3A) on the 15q11-q13 chromosome. The complications of AS are strabismus, atrophy of the optical nerve, and blindness, which are rarely reported. There is a possibility of complications in the laboratory diagnostic tests for AS. One method is to evaluate with DNA methylation analysis of AS/Prader-Willi Syndrome (PWS) imprinting center (IC). On cytogenetic analysis, at least 50–60% of patients had a maternally induced de novo mutation of chromosome 15q11-13 with more serious clinical phenotypes such as microcephaly, seizures, language impairment, and motor difficulties. Multiexonic or whole gene deletion is identified by array-comparative genomic hybridisation (CGH) in some cases and laboratory and methodology may vary such deletions. Diagnosis of AS can be suggested by unsteady movements before walking. Based on the patient’s medical history, electroencephalogram (EEG) data, clinical symptoms, and the presence or absence of a chromosome 50 deletion, a diagnosis of AS is made. Incidence estimated for AS is approximately 1 in 12,000–20,000 birth lives, but the epidemiological measures of life expectancy remains unknown. The clinical features of AS phenotype include seizures, sleep disturbance, intellectual disability, and movement disorders such as tremor and ataxia, anxiety, expressive language is limited, behavioral changes, pleasant demeanor, and easily manipulated laughs, EEG abnormalities were discovered in around 100% of the patients. The researcher identified problems with inflammation at the injection site caused by a higher dose of a drug and they monitored proteins in the individual’s blood and cerebrospinal fluid as an additional safety precaution. Genetic counseling for families with one child with AS to address the likelihood of recurrence can be a challenging subject that frequently requires specialist advice.

Hereditary conditions associated with elevated cancer risk in childhood

The widespread use of next-generation sequencing (NGS) technologies revealed that a significant percentage of tumors in children develop as a part of monogenic hereditary diseases. Predisposition to the development of pediatric neoplasms is characteristic of a wide range of conditions including hereditary tumor syndromes, primary immunodeficiencies, rasopathies, and phakomatosis. The mechanisms of tumor molecular pathogenesis are diverse and include disturbances in signaling cascades, defects in DNA repair, chromatin remodeling, and microRNA processing. Timely diagnosis of tumor-associated syndromes is important for the proper choice of cancer treatment, genetic counseling of families, and the development of surveillance programs. The review describes the spectrum of neoplasms characteristic of the most common syndromes and the molecular pathogenesis of these diseases.

Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism

ObjectivesCHARGE syndrome is a congenital hereditary condition involving multiple systems. Patients are easily misdiagnosed with idiopathic hypogonadotropic hypogonadism (IHH) due to the overlap of clinical manifestations. An accurate clinical diagnosis remains challenging when the predominant clinical manifestation resembles hypogonadotropic hypogonadism. MethodsThis original research is conducted based on the genetic finding and analysis of clinical cases. Whole-exome sequencing (WES) and in-silico analyse were performed on two sisters to investigate the pathogenesis in this family. Homology modelling was conducted to evaluate structural changes in the variants. ResultsWES and Sanger sequencing revealed two siblings carrying a nonsense mutation (NM_017780.4: c.115C > T) in exon 2 of CHD7 inherited from a mildly affected mother and a missense mutation (NM_015295.3: c.2582T > C) in exon 20 of SMCHD1 inherited from an asymptomatic father. The nonsense mutation in CHD7 was predicted to generate nonsense-mediated decay, whereas the missense mutation in SMCHD1 decreased protein stability. ConclusionsWe identified digenic CHD7 and SMCHD1 mutations in IHH-associated diseases for the first time and verified the synergistic role of oligogenic inheritance. It was also determined that WES is an effective tool for distinguishing diseases with overlapping features and establishing a molecular diagnosis for cases with digenic or oligogenic hereditary disorders, which is beneficial for timely treatment, and family genetic counseling.

Sequence variants in different genes underlying Bardet-Biedl syndrome in four consanguineous families.

Bardet-Biedl Syndrome (BBS) is a rare (1:13,500-1-160,000) heterogeneous congenital disorder, characterized by postaxial polydactyly, obesity, hypogonadism, rod-cone dystrophy, cognitive impairment, and renal abnormalities (renal cystic dysplasia, anatomical malformation). To date about twenty-five genes have been identified to cause BBS, which accounts for about 80% of BBS diagnosis. In the current study, we have performed mutational screening of four Pakistani consanguineous families (A-D) with clinical manifestation of BBS by microsatellite-based genotyping and whole exome sequencing. Analysis of the data revealed four variants, including a novel/unique inheritance pattern of compound heterozygous variants, p.(Ser40*) and p.(Thr259Leufs*21), in MKKS gene, novel homozygous variant, p.(Gly251Val)] in BBS7 gene and two previously reported p.(Thr259Leufs*21) in MKKS and p.(Met1Lys) in BBS5 gene. The variants were found segregated with the disorder within the families. The study not only expanded mutations spectrum in the BBS genes, but this will facilitate diagnosis and genetic counselling of families carrying BBS related phenotypes in Pakistani population.

Novel PPP1R21 mutation in a family with autosomal recessive neurodevelopmental disorder: results of genomics and molecular analysis

BackgroundNeurodevelopmental diseases are a group of disorders affecting the development of the nervous system and brain function. In particular, neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities is a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss-of-function variants. This study aimed to investigate the molecular etiology of this neurodevelopmental disorder in an Iranian patient from a consanguineous marriage family.Methods and resultsAfter clinical examination and DNA sampling, whole exome sequencing was performed for the patient. The findings were confirmed and segregated via Sanger sequencing and bioinformatics approach in the patient and parents, respectively. We identified the novel loss-of-function mutation of c.1317_1318delAG p.(Asp440Tyrfs*6) in PPP1R21 gene in our patient suffering from severe developmental delays, mental retardation, facial deformities, muscle weakness, difficulty breathing and feeding, and vision impairment. Through Sanger sequencing, the homozygous and heterozygous statuses of this variant were observed in the patient and the parents, respectively. As well, the bioinformatics approach demonstrated the disease-causing effect and clinical pathogenicity of this mutation.ConclusionsSuch findings improve our knowledge of patients with neurodevelopmental phenotypes. In addition, these results can be particularly helpful for prenatal and preimplantation diagnosis and genetic counseling of families with a high risk of infantile intellectual disabilities.

It's Never Too Late for a Diagnosis.

Zellweger spectrum disorder (ZSD) (OMIM#214100) is a phenotypic continuum ranging from severe to mild presentations. ZSD is now used in all individuals with a defect in one of the 13 ZSD-PEX genes, regardless of phenotype. Diagnosis can be suggested by abnormal levels of very long-chain fatty acids, phytanic acid, pristanic acid, plasmalogens, pipecolic acid, or bile acids. However, false negatives are frequent, mostly in older patients. Definite diagnosis is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in one of the 13 ZSD-PEX genes. A 39-year-old female patient had a global development delay since her first year of life. Never developed oral language but had sphincter control and was able to walk and laugh. At 8 years old, she had her first seizure and lost sphincter control when she was 20 years old. At 28 years old, she had an episode of status epilepticus, with severe prostration and became bedridden. She is currently mute, without capacity for communication or motor control. She has no consanguineous parents, has a 35 year old brother with global developmental delay and their mother had a history of an abortion, without other relevant family history. Brain MRI of the patient revealed severe leukodystrophy mainly periventricular, bilateral and symmetric, and less prominent in the cerebellar white matter, with severe cerebral and corpus callosum atrophy. Molecular study with a leukodystrophy gene panela identified a homozygotic pathogenic variant on PEX 1 gene (NM_000466.3) - c.2528G>A (p.(Gly843Asp)), confirming the diagnosis of ZSD. Homozygosity for PEX1 p.Gly843Asp seems to be associated with an intermediate/milder ZSD phenotype,with survival until adulthood. Some patients develop progressive degeneration of CNS myelin, a leukodystrophy pattern, like this patient, which may lead to regression. This girl with ZSD had a rapid and severe loss of previous skills after a seizure. Even though there is no specific treatment for this disease, a correct diagnosiswas very important for the parents and for family genetic counselling.

SAT187 A Case Of CDC73 Mutation Related Primary Hyperparathyroidism With Ectopic Parathyroid Hyperplasia

Abstract Disclosure: T. Wu: None. N. Dhir: None. M. Bollineni: None. Introduction: Primary hyperparathyroidism is the most common cause of hypercalcemia, and most cases are sporadic. However, in 5-10% cases, it may occur as a syndromic and hereditary disease, like Multiple endocrine neoplasia type 1, type 2A, type 4, or CDC73 mutation related hereditary benign or malignant hyperparathyroidism. In patients with severe or early onset primary hyperparathyroidism, screening for genetic etiology should be considered. Case Presentation: A 35-year-old woman with a medical history of hypertension, kidney stones, and post-operative hypothyroidism presented to the endocrinology clinic due to recurrent hyperparathyroidism. She initially had a parathyroidectomy in 2008 and her calcium corrected at that time. She was again diagnosed with hypercalcemia due to primary hyperparathyroidism in 2021. She underwent re-exploration and had a right thyroid lobectomy with removal of three parathyroid glands. Her PTH was still 309 pg/mL (9-77 pg/mL) and calcium was 11.2 mg/dL (8.6-10.5 mg/dL), and she was started on Cinacalcet. The patient continued to have elevated calcium, bone pain, fatigue, and constipation. A 4D CT scan was ordered, which localized activity to a 1.5 cm arterial enhancing nodule in the anterior mediastinum, with intrathymic location. She underwent right video-assisted thoracoscopic total thymectomy with en bloc and the nodule was found to be ectopic parathyroid tissue. Post-operatively, her calcium normalized to 8.6 mg/dL and PTH was undetectable. She underwent genetic testing due to her recurrent hyperparathyroidism, which showed a CDC73 mutation. She is currently on calcitriol and calcium supplements, and serum calcium has been maintained in the low-normal range. Discussion: The CDC73 gene encodes a protein called parafibromin, which acts as a tumor suppressor, prohibiting cells from proliferating. Mutations in this gene are linked to jaw-tumor syndrome, familial isolated primary hyperparathyroidism (FIHP), and parathyroid carcinoma. These three CDC73-related disorders are clinically overlapping and inherited in an autosomal dominant manner. Biallelic mutations of the CDC73 gene are associated with a high risk of parathyroid cancer since the parafibromin protein is usually absent in parathyroid carcinoma and occasionally in atypical adenomas. FIHP tends to have a more severe clinical presentation with earlier onset (younger than 45 years). Additionally, patients with CDC73 related disorders are more prone to developing ossifying fibroma(s) of the jaw, uterine tumors, and various renal lesions. In summary, this case highlights the diagnostic and therapeutic challenges in a patient with persistent primary hyperparathyroidism after a failed second surgery. Genetic testing is vital for early detection, surveillance, and familial genetic counseling in patients with CDC73 related disorders. Presentation: Saturday, June 17, 2023

Exome sequencing in the pediatric neuromuscular clinic leads to more frequent diagnosis of both neuromuscular and neurodevelopmental conditions.

Exome sequencing (ES) has proven to be a valuable diagnostic tool for neuromuscular disorders, which often pose a diagnostic challenge. The aims of this study were to investigate the clinical outcomes associated with utilization of ES in the pediatric neuromuscular clinic and to determine if specific phenotypic features or abnormal neurodiagnostic tests were predictive of a diagnostic result. This was a retrospective medical record review of 76 pediatric neuromuscular clinic patients who underwent ES. Based upon clinical assessment prior to ES, patients were divided into two groups: affected by neuromuscular (n = 53) or non-neuromuscular (n = 23) syndromes. A diagnosis was made in 28/76 (36.8%), with 29 unique disorders identified. In the neuromuscular group, a neuromuscular condition was confirmed in 78% of those receiving a genetic diagnosis. Early age of symptom onset was associated with a significantly higher diagnostic yield. The most common reason neuromuscular diagnoses were not detected on prior testing was due to causative genes not being present on disease-specific panels. Changes to medical care were made in 57% of individuals receiving a diagnosis on ES. These data further support ES as a powerful diagnostic tool in the pediatric neuromuscular clinic and highlight the advantages of ES over gene panels, including the ability to identify diagnoses regardless of etiology, identify genes newly associated with disease, and identify multiple confounding diagnoses. Rapid and accurate diagnosis by ES can not only end the patient's diagnostic odyssey, but often impacts patients' medical management and genetic counseling of families.

Clinical and genetic screening in a large Iranian family with Marfan syndrome: A case study.

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by pathogenic variants of the fibrillin-1-encoding FBN1 gene that commonly affects the cardiovascular, skeletal, and ocular systems. This study aimed to evaluate the clinical features and genetic causes of the MFS phenotype in a large Iranian family. Seventeen affected family members were examined clinically by cardiologists and ophthalmologists. The proband, a 48-year-old woman with obvious signs of MFS, her DNA sample subjected to whole-exome sequencing (WES). The candidate variant was validated by bidirectional sequencing of proband and other available family members. In silico analysis and molecular modeling were conducted to determine the pathogenic effects of the candidate variants. The most frequent cardiac complications are mitral valve prolapse and regurgitation. Ophthalmic examination revealed iridodonesis and ectopic lentis. A heterozygous missense variant (c.2179T>C/p.C727R) in exon 19 of FBN1 gene was identified and found to cosegregate with affected family members. Its pathogenicity has been predicted using several in silico predictive algorithms. Molecular docking analysis indicated that the variant might affect the binding affinity between FBN1 and LTBP1 proteins by impairing disulfide bond formation. Our report expands the spectrum of the Marfan phenotype by providing details of its clinical manifestations and disease-associated molecular changes. It also highlights the value of WES in genetic diagnosis and contributes to genetic counseling in families with MFS.

Major Cardiac Events in Patients and Relatives With Hereditary Hypertrophic Cardiomyopathy

BackgroundLittle evidence is available on the disease expression in relatives of index patients with hypertrophic cardiomyopathy (HCM). This information has important implications for family screening programs, genetic counseling, and management of affected families. ObjectivesThe purpose of this study was to investigate the disease expression and penetrance in relatives of index patients carrying pathogenic/likely pathogenic (P/LP) variants in recognized HCM genes. MethodsA total of 453 consecutive and unrelated HCM index patients underwent clinical and genetic investigations. A total of 903 relatives of genotype-positive index patients were invited for clinical investigations and genetic testing. Penetrance, disease expression, and incidence rates of major adverse cardiac events (MACEs) were investigated in individuals carrying P/LP variants. ResultsForty percent (183/453) of index patients carried a P/LP variant. Eighty-four percent (757/903) of all relatives of index patients with P/LP variants were available for the investigation, of whom 54% (407/757) carried a P/LP variant. The penetrance of HCM among relatives was 39% (160/407). Relatives with HCM and index patients were diagnosed at a similar age (43 ± 18 years vs 46 ± 15 years; P = 0.11). There were no differences in clinical characteristics or incidence rates of MACE during 8 years of follow-up. ConclusionsThe disease expression of HCM among index patients and affected relatives carrying P/LP variants in recognized disease genes was similar, with an equal risk of experiencing MACE. These findings provide evidence to support family screening and follow-up of genotype-positive HCM families to improve management and diminish the number of adverse disease complications among relatives.

Genome-wide CNV analysis uncovers novel pathogenic regions in cohort of five multiplex families with neurodevelopmental disorders

Structural reorganization of chromosomes by genomic duplications and/or deletions are known as copy number variations (CNVs). Pathogenic and disease susceptible CNVs alter gene dosage and its phenotypic expression that often leads to human genetic diseases including Neurological disorders. CNVs affecting same common genes in multiple neurodevelopmental disorders can better explain the shared clinical and genetic aetiology across brain diseases. Our study presents the novel copy number variations in a cohort of five multiplex consanguineous families with intellectual disability, microcephaly, ASD, epilepsy, and neurological syndromic features. Cytoscan HD microarray suite has revealed genome wide deletions, duplications and LOH regions which are co-segregating in the family members for the rare neurodevelopmental syndromic phenotypes. This study identifies 1q21.1 microduplication, 16p11.2 microduplication, Xp11.22 microduplication, 4p12 microdeletion and Xq21.1 microdeletion that significantly contribute to primary disease onset and its progression for the first time in Pakistani families. Our study has potential impact on the understanding of pathogenic genetic predisposition for appearance of complex and heterogeneous neurodevelopmental disorders with otherwise unexplained syndromic features. Identification of altered gene dosage across the genome is helpful in improved diagnosis, better disease management in day-to-day life activities of patients with cognitive impairment and genetic counselling of families where consanguinity is a tradition. Our study will contribute to expand the knowledge of genotype-phenotype expression and future gateways in therapeutics and precision medicine research will be open in Pakistan.

Genetic Spectrum of Congenital Anomalies of the Kidney and Urinary Tract in Chinese Newborn Genome Project

Congenital anomalies of the kidney and urinary tract (CAKUT) corresponds to a spectrum of defects. Several large-cohort studies have used high-throughput sequencing to investigate the genetic risk of CAKUT during antenatal, childhood, and adulthood period. However, our knowledge of newborns with CAKUT is limited. This multicenter retrospective cohort study explored the genetic spectrum of CAKUT in a Chinese neonatal cohort. Clinical data and whole exome sequencing (WES) data of 330 newborns clinically diagnosed with CAKUT were collected. WES data were analyzed for putative deleterious single nucleotide variants (SNVs) and potential disease-associated copy number variants (CNVs). In this study, pathogenic variants were identified in 61 newborns (18.5%, 61/330), including 35 patients (57.4%) with SNVs, 25 patients (41%) with CNVs, and 1 patient with both an SNV and a CNV. Genetic diagnosis rates were significantly higher in patients with extrarenal manifestations (P＜0.001), especially in those with cardiovascular malformations (P＜0.05). SNVs in genes related to syndromic disorders (CAKUT with extrarenal manifestations) were common, affecting 20 patients (57.1%, 20/35). KMT2D was the most common gene (5 patients) and 17q12 deletion was the most common CNV (4 patients). Patient 110 was detected with both a CNV (17q12 deletion) and an SNV (a homozygous variant of SLC25A13). Among the newborns with positive genetic results, 22 (36.1%, 22/61) patients may benefit from a molecular diagnosis and change in clinical management (including early multidisciplinary treatment, disease-specific follow-up, and familial genetic counseling). This study shows the heterogeneous genetic etiologies in a Chinese CAKUT neonatal cohort by using WES. Patients with CAKUT who have extrarenal manifestations are more likely to harbor genetic diagnoses. Kabuki syndrome and 17q12 deletion syndrome were the most common genetic findings. Approximately 36.1% of the patients may benefit from molecular diagnoses and a change in clinical management.

Acute hepatic porphyrias: Recommendations for diagnosis and management with real-world examples

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease.

Identification of variants in genes associated with hypertrophic cardiomyopathy in Mexican patients

The objective of this work was to identify genetic variants in Mexican patients diagnosed with hypertrophic cardiomyopathy (HCM). According to world literature, the genes mainly involved are MHY7 and MYBPC3, although variants have been found in more than 50 genes related to heart disease and sudden death, and to our knowledge there are no studies in the Mexican population. These variants are reported and classified in the ClinVar (PubMed) database and only some of them are recognized in the Online Mendelian Information in Men (OMIM). The present study included 37 patients, with 14 sporadic cases and 6 familial cases, with a total of 21 index cases. Next-generation sequencing was performed on a predesigned panel of 168 genes associated with heart disease and sudden death. The sequencing analysis revealed twelve (57%) pathogenic or probably pathogenic variants, 9 of them were familial cases, managing to identify pathogenic variants in relatives without symptoms of the disease. At the molecular level, nine of the 12 variants (75%) were single nucleotide changes, 2 (17%) deletions, and 1 (8%) splice site alteration. The genes involved were MYH7 (25%), MYBPC3 (25%) and ACADVL, KCNE1, TNNI3, TPM1, SLC22A5, TNNT2 (8%). In conclusion; we found five variants that were not previously reported in public databases. It is important to follow up on the reclassification of variants, especially those of uncertain significance in patients with symptoms of the condition. All patients included in the study and their relatives received family genetic counseling.