A novel IGF2/H19 domain triplication in the 11p15.5 imprinting region causing either Beckwith-Wiedemann or Silver-Russell syndrome in a single family.

Defects of 11p15.5 imprinting result in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome (BWS) characterized by overgrowth and Silver-Russell syndrome (SRS) associated with growth retardation. In a small group of patients with BWS and SRS, copy number variations (CNVs) involving the 11p15.5 region are observed; and their effects depend on the localization, size, and the parental mode of transmission. We report a novel IGF2/H19 domain cis-triplication in the 11p15.5 region identified in a girl with BWS and her father with symptoms of SRS. To the best of our knowledge, this is the first report of IGF2/H19 domain triplication associated with BWS or SRS and the second report of an additional copy of this region in an individual with clinical features of SRS. This study shows that paternal IGF2/H19 domain triplication results in BWS, gives additional support to the hypothesis that the maternal amplification of IGF2/H19 domain may lead to the manifestation of SRS and underlines difficulties of genetic counseling in patients with CNVs involving the 11p15.5 region. © 2016 Wiley Periodicals, Inc.

11p15 duplication and 13q34 deletion with Beckwith-Wiedemann syndrome and factor VII deficiency.

Here we report a patient with 11p15.4p15.5 duplication and 13q34 deletion presenting with Beckwith-Wiedemann syndrome (BWS) and moderate deficiency of factor VII (FVII). The duplication was initially diagnosed on methylation-sensitive multiplex ligation-dependent probe amplification. Array comparative genome hybridization confirmed its presence and indicated a 13q34 distal deletion. The patient's clinical symptoms, including developmental delay and facial dysmorphism, were typical of BWS with paternal 11p15 trisomy. Partial 13q monosomy in this patient is associated with moderate deficiency of FVII and may also overlap with a few symptoms of paternal 11p15 trisomy such as developmental delay and some facial features. To our knowledge this is the first report of 11p15.4p15.5 duplication associated with deletion of 13q34 and FVII deficiency. Moreover, this report emphasizes the importance of detailed clinical as well as molecular examinations in patients with BWS features and developmental delay.

The first case of a patient with de novo partial distal 16q tetrasomy and a data's review.

We report on a patient with severe psychomotor disability, numerous dysmorphic features, and congenital malformations resulting from a complex genomic rearrangement on 16q24.1-q24.3 involving a de novo duplication-triplication pattern. To the best of our knowledge, this is the first reported patient presenting with this aberration within the distal chromosome 16q. We suggest that the clinical phenotype of our patient results from over-dosage of genes mapped to the region with duplication/triplication (five genes: FOXF1, FOXC2, ANKRD11, SPG7 and FANCA seem to play a peculiar role). Detailed molecular characterization and documentation of the complex genomic rearrangement observed in the proband and of the clinical presentation are important for accurate genotype-phenotype correlations in genetic counseling. Delineation of the gene map for the terminal region of chromosome 16q will provide insight into this chromosome 16q24.1-q24.3 contiguous gene duplication-triplication syndrome.

Cardiovascular involvement and prognosis in Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis. AIMS: The study aimed at analysis of clinical data on cardiovascular involvement and management of LDS patients. METHODS: The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery, or otherwise unexplained sudden death. RESULTS: Thirty-four patients from 15 families were included, and five identified variants were novel. Probands' mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity, and tortuosity of cervical arteries were present in 79%, 71%, 68%, and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at a median age of 35 years. The youngest age at AD was 16 years, and 7 years for elective aneurysm repair. Second and third aortic events occurred in 9 and 4 patients, respectively. Eight patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in the presence of skin striae (P = 0.03), tended to be shorter in the presence of Marfanoid features (P = 0.06), and longer with TGFB2 variants (P = 0.06). CONCLUSIONS: LDS is associated with high burden of cardiovascular complications at a young age.

Maternal de novo triple mosaicism for two single OCRL nucleotide substitutions (c.1736A>T, c.1736A>G) in a Lowe syndrome family.

Since the identification of the Lowe's oculocerebrorenal syndrome gene, more than 100 distinct OCRL mutations have been observed. Germline mosaicism has rarely been detected in Lowe families; however, the presence of mosaic mutations, in particular triple mosaicism, may often remain undiagnosed. In the course of OCRL analysis in a Polish family, the index case showed a hemizygous nucleotide transition (c.1736A>G, p.His507Arg). Gene analysis in the patient's mother not only provided evidence that she is a carrier of the mutant allele transmitted to her son but also showed an additional c.1736A>T (p.His507Leu) transversion affecting the same base position. DNA from a mouthwash sample from the mother showed a similar fluorescence intensity pattern at the affected nucleotide. These data, together with the findings that maternal grandparents solely showed wildtype sequence, implied a de novo mosaicism in the mother. Triple X syndrome was ruled out by karyotype analysis and a partial or complete gene duplication could be excluded. Allele-specific amplification confirmed the results of three alleles being present in the mother. The amount of wildtype allele detected in qPCR implied the presence of cells solely harboring c.1736A and single-cell PCR experiments confirmed the presence of non-mutant cells in the mother's blood. These data suggest that the mutations observed are the result of two de novo events in early embryogenesis of the mother. To the best of our knowledge, this is the first observation of triple mosaicism at a single nucleotide.

Clinical characteristics of Polish patients with molecularly confirmed Mowat-Wilson syndrome.

Mowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.

Immune Dysregulation in Patients With Chromosome 18q Deletions-Searching for Putative Loci for Autoimmunity and Immunodeficiency.

Introduction: Autoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions. Material and Methods: Medical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR-a free web resource for gene prioritization. Results: 18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min-max: 4.0-33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls. Conclusions: Patients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.

Rare clinical findings in three sporadic cases of Beckwith-Wiedemann syndrome due to novel mutations in the CDKN1C gene.

Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder characterised by macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralised overgrowth and predisposition to embryonal tumours. BWS results mainly from epigenetic changes at chromosome 11p15.5; however, heterozygous pathogenic variants on the maternal CDKN1C allele are observed in 5-8% of sporadic BWS cases. In this study, we report three sporadic BWS patients with novel pathogenic variants in the CDKN1C gene, including one missense (c.181T>C) and two frameshift (c.415_416dup, c.804delC). Detailed clinical evaluation of the patients showed variable manifestation of the disease and underlined the diagnostic challenge for BWS patients at various age of life. The child with the c.415_416dup variant presented with two rare features observed so far in only a few BWS patients with CDKN1C pathogenic variants: supernumerary flexion creases and agenesis of corpus callosum. Confirmation of these findings in another BWS patient adds to the broad clinical spectrum of the disease and suggests that presence of these features may be associated with CDKN1C pathogenic variants.

Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome.

Costello syndrome (CS) is a rare congenital disorder from the group of RASopathies, characterized by a distinctive facial appearance, failure to thrive, cardiac and skin anomalies, intellectual disability, and a predisposition to neoplasia. CS is associated with germline mutations in the proto-oncogene HRAS, a small GTPase from the Ras family. In this study, a molecular and clinical analysis was carried out in eight Polish patients with the Costello phenotype. A molecular test showed two known heterozygous mutations in the first coding exon of the gene in seven patients: p.G12S (n=4) and p.G12A (n=3), and a novel pathogenic variant p.G60V in one child with an unusually severe, lethal course of the syndrome. In addition, a fatal course of CS was present in one patient with the p.G12A mutation and in another with p.G12S, there was a co-occurrence of Turner syndrome because of the distal Xp deletion. A severe clinical manifestation with a lethal outcome in an individual with p.G60V in HRAS and contrary observations of an attenuated phenotype in CS patients with other mutations at glycine-60 residue may suggest that the nature of the substituted amino acid plays a significant role in the clinical variability observed in some CS cases.

Malan syndrome (Sotos syndrome 2) in two patients with 19p13.2 deletion encompassing NFIX gene and novel NFIX sequence variant.

BACKGROUND AND AIM: Sotos syndrome 2 (MIM #614753), known also as Malan syndrome, is caused by heterozygous mutations/deletions of the NFIX gene located on chromosome 19p13.2. It manifests in developmental delay, intellectual impairment, macrocephaly, central nervous system anomalies, postnatal overgrowth, and craniofacial dysmorphism. Unusual behavior with/without autistic traits, ophthalmologic, gastrointestinal, musculo-skeletal, and hand/foot abnormalities are also frequent. Due to the limited number of such cases, no definitive conclusions about genotype-phenotype correlations have been possible. In the following paper, we discuss physical features consistent with Sotos syndrome 2 based on literature review and two new cases [a patient with de novo 19p13.2 deletion encompassing a part of the NFIX gene and a patient with de novo (not described so far) heterozygous missense mutation c.367C>T (p.Arg123Trp) in the NFIX gene]. RESULTS: Apart from overgrowth and psychomotor developmental delay, the most consistent physical features of our two patients are dysmorphism including high forehead, downslanting palpebral fissures, pointed chin, and abnormalities of the pinna. Both show abnormal behavior and present with long, tapered fingers and toenail defect. No severe congenital malformations were noted. CONCLUSIONS: We hope these data will serve as a material for further studies and provide an opportunity to make more reliable genotype-phenotype correlations.

Oculocutaneous albinism in a patient with 17p13.2-pter duplication - a review on the molecular syndromology of 17p13 duplication.

BACKGROUND: Chromosomal duplications involving 17p13.3 have recently been defined as a new distinctive syndrome with several diagnosed patients. Some variation is known to occur in the breakpoints of the duplicated region and, consequently, in the phenotype as well. AIMS: We report on a patient, the fifth to our knowledge, a 4-year-old girl with a pure de novo subtelomeric 17p13.2-pter duplication. She presents all of the facial features described so far for this duplication and in addition, a unilateral palmar transversal crease and oculocutaneous albinism which has not been reported previously. METHODS: A detailed molecular description of the reported aberration and correlation with the observed phenotypical features based on a literature review. We discuss the possible molecular etiology of albinism in regard to the mode of inheritance. CONCLUSION: The new data provided here may be useful for further genotype correlations in syndromes with oculocutaneous albinism, especially of autosomal dominant inheritance.

Is diagnosing cardio-facio-cutaneous (CFC) syndrome still a challenge? Delineation of the phenotype in 15 Polish patients with proven mutations, including novel mutations in the BRAF1 gene.

Cardio-facio-cutaneous (CFC) syndrome is characterized by a variable degree of developmental delay and congenital anomalies, including characteristic facial, cardiac, and ectodermal abnormalities. It is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. In, however, approximately 10%-30% of individuals with a clinical diagnosis of CFCS, no mutation of the causative gene is found. Therefore, clinical studies in patients with the CFCS spectrum are valuable. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting genes encoding serine/threonine kinases, a group of 15 children and young adults with a diagnosis of CFCS was screened. We documented three novel mutations in the BRAF gene and correlated clinical findings with causative mutations in the BRAF or MEK1/MEK2 genes.

[Assessment of pregnancy and labour outcome and the condition of the newborn in primiparous women aged 35 and older]. / Ocena przebiegu ciazy I porodu oraz stanu noworodka u pierworódek powyzej 34 roku zycia.

OBJECTIVE: To assess the effect of maternally advanced age on pregnancy and labour outcome. MATERIAL AND METHODS: Pregnancies of 95 primiparous women aged 35 or older were compared with pregnancies of 130 women aged 20-30 with respect to pregnancy complications and labour outcome. RESULTS: Women aged 35 or older had cesarean section three times as often as women in the 20-30 year group old. Advanced maternal age compared with younger age was associated with a significantly higher rate of diabetes, hypertensive disorder, thrombocytopenia and intrauterine growth retardation. CONCLUSIONS: Primiparous women aged 35 or older are at an increased risk of complications in pregnancy and are at a higher risk of cesarean section compared with younger women.

Spectrum of JAG1 gene mutations in Polish patients with Alagille syndrome.

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by developmental abnormalities in several organs including the liver, heart, eyes, vertebrae, kidneys, and face. The majority (90-94%) of ALGS cases are caused by mutations in the JAG1 (JAGGED1) gene, and in a small percent of patients (∼1%) mutations in the NOTCH2 gene have been described. Both genes are involved in the Notch signaling pathway. To date, over 440 different JAG1 gene mutations and ten NOTCH2 mutations have been identified in ALGS patients. The present study was conducted on a group of 35 Polish ALGS patients and revealed JAG1 gene mutations in 26 of them. Twenty-three different mutations were detected including 13 novel point mutations and six large deletions affecting the JAG1 gene. Review of all mutations identified to date in individuals from Poland allowed us to propose an effective diagnostic strategy based on the mutations identified in the reported patients of Polish descent. However, the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations.

Four novel RSK2 mutations in females with Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is an X-linked semi-dominant disorder caused by mutations in the RSK2 gene and characterized by moderate to severe mental retardation, characteristic facial features, skeletal deformities, and tapering fingers in males. Females are usually much more mildly and variably affected thus more difficult to diagnose. In this study, molecular genetic analysis was carried out in four female patients presenting features of Coffin-Lowry syndrome. The probands were sporadic cases with no affected males in their families. The molecular analysis of the RSK2 gene revealed four novel mutations, including two frameshift and one missense mutation identified by sequencing, and one large deletion detected by multiplex ligation-dependent probe amplification (MLPA) analysis. Females exhibited a random X-chromosome inactivation pattern. To our knowledge, this is the first report of applying MLPA in the diagnostics of CLS and the first description of a large deletion in a CLS female. These results support including screening for large rearragements in the genetic analysis of female CLS patients.