Genetic Counseling Of Families Research Articles

Causal Variations at IRF6 Gene Identified in Van der Woude Syndrome Pedigrees.

The purpose of this study is to analyze the clinical characteristics of patients with Van der Woude syndrome (VWS) and to detect variations in each patient. Finally, the combination of genotype and phenotype can make a clear diagnosis of VWS patients with different phenotype penetrance. Five Chinese VWS pedigree were enrolled. Whole exome sequencing of the proband was performed, and the potential pathogenic variation was further verified by Sanger sequencing in the patient and their parents. The human mutant IRF6 coding sequence was generated from the human full-length IRF6 plasmid by site-directed mutagenesis and cloned into the GV658 vector, RT-qPCR and Western blot were used to detect the expression of IRF6. We found one de novo nonsense variation (p. Gln118Ter) and three novel missense variations (p. Gly301Glu, p. Gly267Ala, and p. Glu404Gly) co-segregated with VWS. RT-qPCR analysis revealed that p. Glu404Gly significantly reduced the expression level of IRF6 mRNA. Western blot of cell lysates confirmed that IRF6 p. Glu404Gly abundance levels were lower than those for IRF6 wild type. This discovery of the novel variation ( IRF6 p. Glu404Gly) expands the spectrum of known variations in VWS in Chinese humans. Genetic results combined with clinical phenotypes and differential diagnosis points from other diseases can make a definitive diagnosis and provide genetic counseling for families.

A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family

This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected. Further molecular study of targeted sequencing also revealed a RET germline mutation (C634G) in the family tree including the three members with onset of the disease and one granddaughter who had no disease at the time of testing. Despite the syndrome being well-known, it may still be misdiagnosed because of its rarity and long disease onset. A few lessons can be learned from this unique case. Successful diagnosis requires high suspicion and surveillance and a tri-level methodology including a careful review of family history, pathology and genetic counselling.

A clinical case of anosognosia in a CADASIL disease.

IntroductionCADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a cerebrovascular disease, tht appears in 1.98/100,000. It´s caused by a mutation of the Notch3 gene and is characterized by accumulation of granular osmiophilic material in the middle layer of the small and median sized cerebral arteries.Sypmtoms are migraine, recurrent cerebral ischemic episodes, dementia, neuropsychiatric disorders (anosognosia, character disorders, apathy and cognitive impairment). It usually appears between 30-60 years, although there is an important variability. There is no curative treatment, only palliative.ObjectivesClinical review of anosognosia and its presence in CADASIL disease.MethodsClinical case and literatura review.ResultsWe presented the clinical case of a 68-year-old man, who was diagnosed with CADASIL after a stroke 3 years earlier. In his family, his brother was diagnosed also with CADASIL. The patient had previously presented disturbances in impulse control (hyperorality) and important executive failures. He currently presented anosognosia, deficits in verbal memory, spatial perception and executive functions, in addition to behavioral alterations and apathy. Due to these deficits he was prohibited from certain activities (driving, hunting).The patient was not aware of these deficits and becouse of his “no knowledge of his illness”, he disagreed with these prohibitions, so he showed rage and anger at the impotence of not understanding why certain actions are prohibited.In the consultation, mnesic errors and in naming objects were also objectified, for which it was recommended to carry out cognitive stimulation on a daily basis. In addition, he presented failures of sphincter incontinence, especially of urine and occasionally also of the anal sphincter. He had previously had episodes of myoclonus or fasciculations.A genetic study by massive sequencing confirmed the heterozygous presence of the pathogenic variant c.1819C>T p.(Arg607Cys) in the NOTCH3 gene, a CADASIL disease.ConclusionsThe anosognosia that many patients with CADASIL disease present constitutes a problem because it contributes to the delay in consultation and, therefore, the delay in the adequate diagnostic approach, therapeutic possibilities and family genetic counseling. Due in part to anosognosia, CADASIL is considered an underdiagnosed entity. Due to the lack of awareness and the consequent lack of recognition of the deficit, these people are often seen as stubborn and difficult to deal with by people in their immediate environment.In addition, there is general difficulty in the rehabilitation process, since patients do not think the neccesity to be treated. This can generate frustration and despair both in their relatives and in the health personnel.For all these reasons, both in anosognosia and in CADASIL disease, adequate psychological support is needed for both those affected and their families.Disclosure of InterestNone Declared

Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick-Needles syndrome (MNS) in a family with recurrent miscarriage.

Filamin A, encoded by the X-linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick-Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood. We found a family with two consecutive miscarriages of similar fetuses with multiple malformations. DNA was extracted from peripheral blood and tissues, and whole exome sequencing was performed for genetic analysis. Then, we created a C57BL/6 mouse with a point mutation by CRISPR/Cas-mediated genome engineering. The migration of primary abdominal muscle cell was detected by wound healing assay. The first fetus showed congenital hygroma colli and omphalocele identified by ultrasound at 12 wks; the second fetus showed hygroma colli and thoraco abdominoschisis at 12 wks, with a new hemizygous mutation c.4420G>A in exon 26 of the FLNA gene, which is predicted to cause an amino acid substitution (p.Asp1474Asn). The mother and grandmother were both present in the c.4420G>A heterozygous state, and the mother's healthy brother had wild-type FLNA. These FLNA-mutated mice exhibited a broader central gap between the rectus abdominis than the wild type (WT), similar to the midline structure dysplasia of the abdominal wall in the two fetuses. Wound healing assays showed the attenuated migration capacity of abdominal muscle cells in mice with mutated FLNA. Finally, we summarized the cases of MNS with FLNA mutation from the accessible published literature thus far. Our research revealed a mutation site of the FLNA for MNS and explored the mechanism of midline structure dysplasia in the abdominal wall of male patients, which could provide more evidence for the clinical diagnosis and genetic counseling of families with these disorders.

Phelan-McDermid syndrome associated with a novel heterozygous mutation in the SHANK3 gene

Phelan-McDermid syndrome (PMS) is a hereditary disorder associated with microdeletions of chromosome 22q13 or point mutations in SHANK3, characterized by mental and speech delays, intellectual disability, epilepsy and autism spectrum disorder. We describe a case PMS associated with a heterozygous mutation c.2486delC (p.Pro829fs) in SHANK3. The diagnostic pathway of a female patient with PMS took more than 7 years; the reason for treatment was the onset of epileptic seizures and impaired speech development. The existence of different types of rearrangements and genomic variations can explain the high clinical variability observed in individuals with PMS. Only molecular diagnosis can accurately diagnose individuals with PMS for follow-up and medical genetic counselling of families.

Diagnosis of Treacher-Collins Syndrome: The role of the multidisciplinary team in patient management and family genetic counseling

INTRODUCTION: Although Treacher-Collins syndrome has to be considered a differential diagnosis in congenital craniofacial abnormalities, the clinical diagnosis and research related to it still present a gap, especially in African regions. Thus, this work aims at highlighting this syndrome's clinical features for raising medical awareness. CLINICAL CASE: We reviewed a 1-year-old patient referred to our clinical genetic unit at Rwanda military hospital, Kigali, Rwanda. Physical examinations indicated severe craniofacial abnormalities, including downward-sloping eyes, slight notching of the lower lids, small and underdeveloped eyebrow bones, vision problems, small outer ears, small and underdeveloped cheekbones, and jaw. Within the limits of the techniques used in our laboratory, the cytogenetic analysis revealed a normal karyotype, 46, XY. CONCLUSION: The patient was diagnosed with Treacher-Collins syndrome based on clinical manifestations of craniofacial features. Nevertheless, laboratory tests performed were limited to karyotyping and should not detect any gene defect. Long-term follow-up of the patient and his family was recommended. Further molecular analyses should be performed to identify causing genetic mutation mainly in the TCOF1, POLR1C, or POLR1D genes.

Not just a carrier: Clinical presentation and management of patients with heterozygous disease-causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening.

Hypophosphatasia (HPP) is an underrecognized, complex bone mineralization disorder with variable manifestations caused by one or two deleterious variants in the alkaline phosphatase (ALPL) gene. Expanded carrier screening (ECS), inclusive of ALPL, intends to inform reproductive risk but may incidentally reveal an HPP diagnosis with 50% familial risks. We sought to investigate at-risk individuals and develop a multidisciplinary referral and evaluation protocol for ECS-identified ALPL heterozygosity. A retrospective database query of ECS results from 8 years to 1 month for heterozygous pathogenic/likely pathogenic ALPLvariants was completed. We implemented a clinical protocol for diagnostic testing and imaging, counseling, and interdisciplinary care management for identified patients, and outcomes were documented. Heterozygous ALPL variants were identified in 12/2248 unrelated patients undergoing ECS (0.53%; heterozygote frequency 1/187). Of 10 individuals successfully contacted, all demonstrated symptomatology and/or alkaline phosphatase values consistent with HPP. ECS may reveal incidental health risks, including recognition of missed HPP diagnoses in ALPL heterozygotes. In our cohort, all ECS-identified ALPL heterozygotes with clinical and/or biochemical data available demonstrated features of HPP. Referral to a genetics professional familiar with HPP is indicated for family history assessment, genetic counseling, cascade testing, and long-term bone health management.

First Description of a Frameshift PAX5 Germline Variant in Two Siblings with B-Cell Precursor Acute Lymphoblastic Leukemia

Introduction: Recent studies have highlighted that about 5% of children with Acute Lymphoblastic Leukemia (ALL) carry a germline mutation that predispose to leukemogenesis. PAX5 somatic mutations are frequently identified on sporadic B-ALL, but recently pathogenic PAX5 germline variants have been described in families with recurrence of B-ALL (Shah et al. 2013; Auer et al. 2014; Yazdanparast et al. 2015, Duployez et al. 2021). We describe the case of two siblings both affected by B-ALL with evidence of a new familial PAX5 variant. Case A was a male, 13 years old, diagnosed with B-II ALL. He was enrolled into the AIEOP-BFM ALL 2009 treatment protocol and according to minimal residual disease (MRD) levels he was stratified as medium risk. Eight years later, his sister (14yrs, named as case B) was diagnosed with B-II ALL, and stratified in the medium risk group of AIEOP-BFM ALL 2017 protocol. The two patients were otherwise healthy and borne from healthy unrelated parents; no history of hematological malignancies was reported across the pedigree. Methods: We performed a custom Next Generation Sequencing ALL predisposition panel on DNA extracted from bone marrow samples of both disease onset and remission phase (defined as negativity by PCR-MRD, 10-4 sensitivity). The libraries were performed following Nextera Flex for Enrichment and sequenced on Illumina Nextseq550 platform; the analyses were carried out by Congenica software. The variants of interest were validated and investigated in the family pedigree through PCR and Sanger sequencing. Digital-MLPA testing 55 ALL hot spot genes (including all PAX5 exons) was performed. Results: Through the NGS analysis, we showed that both patients shared a novel germline heterozygous PAX5 variant (c.548delG, p.Gly183AlafsTer84); moreover, the disease samples of both patients carried an additional somatic PAX5 variant (c.239C>G, p.Pro80Arg; variant fraction: 29% in Case A and 38% in Case B). The Digital-MLPA using the ALL panel, excluded the presence of shared copy number alterations (CNV) and, specifically, did not identified CNV alterations involving the PAX5 locus. The familiar segregation showed a paternal origin of the germline PAX5 variant (p.Gly183AlafsTer84); the mother was found to be wild-type. The PAX5 variant was also found in the DNA sample of the patients' grandmother of the paternal branch; a healthy brother of probands (24 years old) was not tested. To investigate a possible impairment of PAX5 function in the development of the B-cell lineage, we evaluated in both parents the B-cell repertoire on peripheral blood fresh mononuclear cells by FACS analysis. Interestingly, the father has a significant reduction on mature IgD+/CD27+ B-cells with a concomitant accumulation of IgD+/CD27- naïve B-cells. Conclusions: We are reporting a novel germline PAX5 p.Gly183AlafsTer84 in a family with recurrence of B-ALL. In contrast to the previous PAX5 described cases that carry an inherited missense variant resulting in a modest attenuation of PAX5 activity, our patients present a germline frameshift variant that brings to premature stop of the protein, suggesting a more destructive impact on PAX5 activity. As in the other reported cases, our patients presented an additional somatic event on PAX5 that further compromise PAX5 function, leading to the establishment of the leukemic clone. Interestingly and different from the literature, the two siblings share the same PAX5 p.Pro80Arg somatic variant, that has been characterized by Gu as a pathogenic variant impairing B lymphoid development and promoting leukemogenesis (Gu et al. 2019). The detailed molecular characterization, including Whole Transcriptome NGS analysis, is ongoing to investigate whether a PAX5-specific signature can be identified. Moreover, a single-cell NGS approach on remission samples of the two siblings could help to identify specific important pathways and altered gene suppression profiles, preceding full leukemia. Consent-dependent characterization of additional family members are ongoing to assess the penetrance of leukemia associated to this new variant and possible additional features. The identification and characterization of germline PAX5 variants is of high interest in the context of leukemia predisposition because of its clinical implications in terms of familial genetic counselling and because of its contribution in the understanding ALL pathogenesis.

Adult-Onset Hereditary Spastic Paraplegia 15 in a Saudi Patient with A Compound Heterozygous Variant in the ZFYVE26Gene.

Hereditary spastic paraplegia (HSP) 15 is an autosomal recessive neurodegenerative disease caused by homozygous or heterozygous point mutations in the ZFYVE26 gene that encodes the spastizin protein, located on chromosome 14q22-q24. Hereditary spastic paraplegia has been rarely reported in Saudi Arabia. In this article, we reported a rare case of adult-onset HSP 15 with a pure form of the disease in a Saudi patient with a compound heterozygous variant in the ZFYVE26 gene. The present case suggests that a compound heterozygous mutation in the ZFYVE26 may be associated with a later-onset disease and a milder phenotype. Given the low prevalence of the disease as well as heterogenicity and variability of its presenting symptoms, HSP 15 may be difficult to diagnose. However, early diagnosis is important to prevent unnecessary extensive investigations, facilitate early symptomatic management and provide genetic counseling for family planning to those affected and their first and second-degree relatives.

Novel copy number variation of COLQ gene in a Moroccan patient with congenital myasthenic syndrome: a case report and review of the literature

BackgroundCongenital myasthenic syndromes (CMSs) are rare genetic diseases due to abnormalities of the neuromuscular junction leading to permanent or transient muscle fatigability and weakness. To date, 32 genes were found to be involved in CMSs with autosomal dominant and/or recessive inheritance patterns. CMS with acetylcholinesterase deficiency, in particular, was determined to be due to biallelic mutations of COLQ gene with early-onset clinical signs. Here, we report clinical features and novel molecular findings of COLQ-related CMS in a Moroccan patient with a review of the literature for this rare form.Case presentationIn this study, we report the case of a 28-month-old Moroccan female patient with hypotonia, associated to axial muscle weakness, global motor delay, bilateral ptosis, unilateral partial visual field deficiency with normal ocular motility, and fatigable muscle weakness. Clinical exome sequencing revealed a novel homozygous deletion of exon 13 in COLQ gene, NM_005677.4(COLQ):c.(814+1_815-1)_(954+1_955-1) del p.(Gly272Aspfs*11). This finding was subsequently confirmed by quantitative real-time PCR (qPCR) in the proband and her parents. In silico analysis of protein-protein interaction network by STRING tool revealed that 12 proteins are highly associated to COLQ with an elevated confidence score. Treatment with Salbutamol resulted in clear benefits and recovery.ConclusionsThis clinical observation illustrates the important place of next-generation sequencing in the precise molecular diagnosis of heterogeneous forms of CMS, the appropriate management and targeted treatment, and genetic counseling of families, with a better characterization of the mutational profile of this rare disease in the Moroccan population.

The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism

Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.

Exome sequencing reveals the first intragenic deletion in ABCA5 underlying autosomal recessive hypertrichosis.

Hereditary hypertrichosis (HH) is characterized by excessive hair growth on various body areas, which is independent of the individual's age. This rare hair disorder has been classified by its origin (genetic or acquired), age of onset, breadth of hair distribution (universal or localized) and the affected body areas. HH is often linked to several additional congenital abnormalities involving teeth, heart and bones. Human HH is associated with heterozygous genomic duplications and deletions in the chromosomal region 17q24.2-q24.3, containing genes such as ABCA5, ABCA6, ABCA10 and MAP2K6. Recently, a homozygous splice-site variant in ABCA5 has been reported to cause autosomal recessive congenital generalized hypertrichosis terminalis (CGHT; OMIM 135400). To investigate the clinical and genetic basis of autosomal recessive hypertrichosis in a large consanguineous Pakistani family. In the present study, we characterized a family of Pakistani origin segregating CGHT in an autosomal recessive pattern, using whole exome sequencing followed by Sanger sequencing RESULTS: We identified a novel 2-bp intragenic deletion [NM_172232.4(ABCA5);c.977_978delAT] causing a frameshift variant (p.His326ArgfsTer5) in ABCA5. To our knowledge, this is the first intragenic deletion in ABCA5 underlying CGHT. The findings further validate the involvement of ABCA5 in hair development. The study will facilitate genetic counselling of families carrying CGHT-related features in Pakistani and other populations.

12q21 Interstitial Deletions: Seven New Syndromic Cases Detected by Array-CGH and Review of the Literature.

Interstitial deletions of the long arm of chromosome 12 are rare, with a dozen patients carrying a deletion in 12q21 being reported. Recently a critical region (CR) has been delimited and could be responsible for the more commonly described clinical features, such as developmental delay/intellectual disability, congenital genitourinary and brain malformations. Other, less frequent, clinical signs do not seem to be correlated to the proposed CR. We present seven new patients harboring non-recurrent deletions ranging from 1 to 18.5 Mb differentially scattered across 12q21. Alongside more common clinical signs, some patients have rarer features such as heart defects, hearing loss, hypotonia and dysmorphisms. The correlation of haploinsufficiency of genes outside the CR to specific signs contributes to our knowledge of the effect of the deletion of this gene-poor region of chromosome 12q. This work underlines the still important role of copy number variations in the diagnostic setting of syndromic patients and the positive reflection on management and family genetic counseling.

Myoclonic epilepsy with ragged red fibers in childhood

Myoclonic epilepsy with ragged red fibers (MERRF) is a maternally inherited disease characterized by myoclonic epilepsy, cerebellar ataxia and progressive muscle weakness. Development of the disease is associated with the most common (90% of cases) point mutation at position 8344 in the mitochondrial lysine transport RNA gene – MTTLys. The disease diagnostics causes certain difficulties due to the insufficient awareness of this pathology and polymorphism of clinical manifestations. The article presents a brief review of the literature data on current views on the disease pathogenesis, diagnostic methods and opportunities for drug treatment, and describes a clinical observation of a 7-year-old child with MERRF syndrome caused by a point mutation at position 8344 in the MTTLys gene. The girl was under dynamic supervision at the neuropsychiatric department. A comprehensive clinical, laboratory and instrumental examination was carried out that also included molecular genetic testing. The progredient progression and multiple symptoms of the disease, slightly increased lactate acidosis in the absence of typical neuroimaging and electromyographic changes are of interest in the observation, thereby confirming they might not necessarily be observed in MERRF. Intrafamily clinical diversity was noted in the absence of signs of the disease in paired mother. A highly informative method of MERRF diagnostics is provided by molecular genetic testing. Establishing a genetic diagnosis underlies a need for conducting medical and genetic counseling for family planning to prevent the re-birth of other sick siblings inheriting this pathology.

Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort

AimEarly-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS. MethodsPatients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years. ResultsThe analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC. ConclusionThe study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.

Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes for 20 families with familial exudative vitreoretinopathy

BackgroundFamilial exudative vitreoretinopathy (FEVR) is a complex form of blindness-causing retinal degeneration. This study investigated the potential disease-causing variants in 20 Chinese families with FEVR.MethodsAll available family members underwent detailed ophthalmological examinations, including best-corrected visual acuity and fundus examination. All probands and most family members underwent fluorescein fundus angiography. Twenty probands underwent whole exome sequencing; 16 of them also underwent copy number variant and mitochondrial genome analysis. Bioinformatics analysis and Sanger sequencing of available family members were used to confirm the disease-causing gene variant.ResultsTwenty families were diagnosed with FEVR based on clinical symptoms, fundus manifestations, and fundus fluorescein angiography. Whole exome sequencing revealed 14 variants in NDP, FZD4, LRP5, and TSPAN12 genes among the 13 families. These variants were predicted to be damaging or deleterious according to multiple lines of prediction algorithms; they were not frequently found in multiple population databases. Seven variants had not previously been reported to cause FEVR: c.1039T>G p.(Phe347Val) in the FZD4 gene; c.1612C>T p.(Arg538Trp) and c.3237-2A>C in the LRP5 gene; and c.77T>A p.(Ile26Asn), c.170dupT p.(Leu57Phe fsTer60), c.236T>G p.(Met79Arg) and c.550dupA p.(Arg184Lys fsTer16) in the TSPAN12 gene. We did not detect any variants in the remaining seven families.ConclusionsThese results expand the spectrum of variants in the NDP, FZD4, LRP5, and TSPAN12 genes and provide insights regarding accurate diagnosis, family genetic counseling, and future gene therapy for FEVR.

Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita.

Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population.

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

Analysis of familial cases of primary immunodeficiency in the context of genetic counseling

Primary immunodeficiencies (PID) are caused by defects in genes of immune system. The mutations may occur de novo or can be inherited. The frequency of familial PID cases varies in different populations and depends on multiple factors. The aim of this study was to analyze familial PID cases among pediatric patients from NMRCPHOI D. Rogachev. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. 1075 children from 1020 families with molecular PID diagnosis were analyzed retrospectively. One hundred and forty-six children had at least one relative with the same disorder; mutations were identified in 31 PID’s genes. The frequency of familial cases was 13.6%. The proportion of families with two or more affected children was 5.4%. Patients born in a consanguineous marriage made up 3% of the observed children. Autosomal dominant PID were typical for families with affected adult relatives. Because of the high amount of familial cases, all parents of children with PID as well as adult PID patients of childbearing age should seek a familial genetic counselling immediately after the corresponding diagnosis. Patients whose PID diagnosis has not been genetically verified, should be urgently tested to find an underlying molecular genetic cause of the disease. Prenatal/preimplantation diagnostic and screening of their close relatives are very important in these families.

Orphan diseases (mucopolysaccharidosis) and damage of the cardiovascular system. Literature review

The paper presents literature data, outlining topical issues of the cardiovascular pathology at mucopolysaccharidosis. It is damage to the heart and blood vessels, one of the cardinal signs of this pathology, that is often fatal. Cardiac pathology is recorded in all types of mucopolysaccharidosis, but it is most significant for patients with three clinical variants of Hurler syndrome, Hunter, and Maroteaux–Lamy syndromes. Typical signs of damage to the cardiovascular system in mucopolysaccharidosis are thickening of the valves with the development of their dysfunction (while the severity of damage to the left‑sided valves is more pronounced), myocardial hypertrophy, conduction disturbance, coronary artery disease, arterial hypertension. Many researchers emphasize the difficulties of clinical and functional examination of the cardiovascular system in patients with mucopolysaccharidosis, which is due to the presence of physical and intellectual limitations in patients, and a gradual symptoms aggravation. For the treatment of cardiovascular pathology at mucopolysaccharidosis, medical and surgical methods are used, including enzyme replacement therapy and stem cell transplantation.
 Gene therapy is considered one of the priority areas in the treatment of mucopolysaccharidosis. Significant progress in this aspect has been achieved with the use of viral vectors under experimental conditions in mice with mucopolysaccharidosis type VII. The basis of mucopolysaccharidosis prevention is medical and genetic counseling of families with subsequent prenatal diagnosis using molecular genetic methods (eg, DNA diagnosis). Thus, early diagnosis and timely pathogenetic treatment of mucopolysaccharidosis will help to prevent disability and adequate integration into society, and effective medical and genetic counseling of families will significantly reduce the incidence of new cases of these severe inherited diseases.