Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.

Characteristic dental pattern with hypodontia and short roots in Fraser syndrome.

Fraser syndrome (FS) is a rare autosomal recessive multiple congenital malformation syndrome characterized by cryptophthalmos, cutaneous syndactyly, renal agenesis, ambiguous genitalia, and laryngotracheal anomalies. It is caused by biallelic mutations of FRAS1, FREM2, and GRIP1 genes, encoding components of a protein complex that mediates embryonic epithelial-mesenchymal interactions. Anecdotal reports have described abnormal orodental findings in FS, but no study has as yet addressed the orodental findings of FS systematically. We reviewed dental radiographs of 10 unrelated patients with FS of different genetic etiologies. Dental anomalies were present in all patients with FS and included hypodontia, dental crowding, medial diastema, and retained teeth. A very consistent pattern of shortened dental roots of most permanent teeth as well as altered length/width ratio with shortened dental crowns of upper incisors was also identified. These findings suggest that the FRAS1-FREM complex mediates critical mesenchymal-epithelial interactions during dental crown and root development. The orodental findings of FS reported herein represent a previously underestimated manifestation of the disorder with significant impact on orodental health for affected individuals. Integration of dentists and orthodontists into the multidisciplinary team for management of FS is therefore recommended.

Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene.

We report on two unrelated families of Polish origin with variable expression of Fraser syndrome (FS; MIM#219000) due to homozygosity for the same pathogenic variant, c.6963_6964dup, of FRAS1. In one family, the disorder presented with perinatal and prenatal lethality. One affected female from family 2 who was followed-up for 32 years, represented a relatively favorable long-term outcome. She displayed the typical craniofacial dysmorphism, including right cryptophthalmos, cutaneous syndactyly, abnormalities of the stomathognatic system, bilateral atresia of the external ear canals resulting in conductive hearing loss, and malformations of the larynx, spleen, kidney, and genitourinary tract. Her intellectual capacities were normal. Our observations illustrate that expression and severity of FS, even when caused by the same pathogenic variant, may be quite different ranging from a lethal disorder to a condition with multiple physical malformations but normal psychomotor development. In addition, we propose that the FRAS1 c.6963_6964dup variant may be a founder mutation in the Polish population. Therefore, it would be reasonable to test specifically for this variant first in any FS1 patient of Polish ancestry.

A 23-year follow-up of a male with Hajdu-Cheney syndrome due to NOTCH2 mutation.

We present a natural history of a 32-year-old man with Hajdu-Cheney syndrome (HJCYS), because of the de novo truncating mutation in the exon 34 of NOTCH2 (c.6424-6427delTCTG, p.Ser2142ArgfsX4), who has been followed up for a period of 23 years (between 9 and 32 years). During follow-up, we observed abnormalities of vision, hearing, voice, and progression of craniofacial features in the form of skeletal dysplasia with affected skull, dentition, spine, limbs, fingers, and toes. Low bone mineral density and history of fragility fractures also suggested primary osteoporosis being a clinical manifestation. According to Stengel-Rutkowski, Schimanek, and Wernheimer (1984; Human Genetics, 6, 272-295), systematic data acquisition has been used for quantitative analysis of anthropological, radiographic, and clinical features at childhood, adolescence, and young adulthood separately. A detailed phenotype description together with the results of reanalysis of 14 reports so far published on patients with HJCYS and NOTCH2 mutation showed similar phenotype evolution with age. The spectrum of observed features may improve diagnostic tools for HJCYS at different periods of the lifespan.

ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a ß1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Meiotic and pedigree segregation analyses in carriers of t(4;8)(p16;p23.1) differing in localization of breakpoint positions at 4p subband 4p16.3 and 4p16.1.

PURPOSE: The purpose of this study was to compare meiotic segregation in sperm cells from two carriers with t(4;8)(p16;p23.1) reciprocal chromosome translocations (RCTs), differing in localization of the breakpoint positions at the 4p subband-namely, 4p16.3 (carrier 1) and 4p16.1 (carrier 2)-and to compare data of the pedigree analyses performed by direct method. METHODS: Three-color fluorescent in situ hybridization (FISH) on sperm cells and FISH mapping for the evaluation of the breakpoint positions, data from pedigrees, and direct segregation analysis of the pedigrees were performed. RESULTS: Similar proportions of normal/balanced and unbalanced sperm cells were found in both carriers. The most common was an alternate type of segregation (about 52 % and about 48 %, respectively). Unbalanced adjacent I and adjacent II karyotypes were found in similar proportions about 15 %. The direct segregation analysis (following Stengel-Rutkowski) of the pedigree of carriers of t(4;8)(p16.1;p23.1) was performed and results were compared with the data of the pedigree segregation analysis obtained earlier through the indirect method. The probability of live-born progeny with unbalanced karyotype for carriers of t(4;8)(p16.1;p23.1) was moderately high at 18.8 %-comparable to the value obtained using the indirect method for the same carriership, which was 12 %. This was, however, markedly lower than the value of 41.2 % obtained through the pedigree segregation indirect analysis estimated for carriers of t(4;8)(p16.3;p23.1), perhaps due to the unique composition of genes present within the 4p16.1-4p 16.3 region. CONCLUSIONS: Revealed differences in pedigree segregation analysis did not correspond to the very similar profile of meiotic segregation patterns presented by carrier 1 and carrier 2. Most probably, such discordances may be due to differences in embryo survival rates arising from different genetic backgrounds.

Co-segregation of Freiberg's infraction with a familial translocation t(5;7)(p13.3;p22.2) ascertained by a child with cri du chat syndrome and brachydactyly type A1B.

The identification of chromosomal breakpoints in association with human abnormal phenotypes can enable elucidation of gene function. We report on epiphyseal aseptic necrosis of the lesser head of the second metatarsal bone, known as Freiberg's infraction (FI), in two female carriers of the apparently balanced t(5;7)(p13.3;p22.2) ascertained by a 16-year-old girl with cri-du-chat syndrome and unusual skeletal features in association with an unbalanced translocation der(5) t(5;7)(p13.3;p22.2). Mapping of the chromosome breakpoints using fluorescent in situ hybridization (FISH) narrowed them to the coding sequence of ADAMTS12 on chromosome 5p13.3 and SDK1 on 7p22.2. In addition, several skeletal abnormalities classified as brachydactyly type A1B (BDA1B) were present in the proband and in both carriers of t(5;7)(p13.3;p22.2), suggesting a potential role of ADAMTS12 in the development of the BDA1B observed in this family.

[Systemic sclerosis. Part 2. Epigenetic factors in the pathogenesis of clinical manifestations]. / Twardzina ukladowa. Czesc 2. Czynniki epigenetyczne w patogenezie objawów klinicznych.

Systemic sclerosis is a complex autoimmune disease characterized by immune activation, fibrosis of the skin and internal organs and vasculopathy affecting predominantly the microvessels with a predilection for women. The genetic background of systemic sclerosis is still full of unanswered questions, with classical genetics able to explain only some systemic sclerosis cases. Novel advances concerning epigenetics give us new insight into pathogenesis of systemic sclerosis. This review focuses on results of recent reports on epigenetic modifications of the gene functions and X inactivation changes in pathogenesis of systemic sclerosis. Current evidence demonstrates DNA heavy methylation (FLI1, NOS3, BMPRII) and hypomethylation of regulatory genes (CD40L, CD70), histone code modifications, abnormal expression of large spectrum of microRNAs.

Recurrence risks for different pregnancy outcomes and meiotic segregation analysis of spermatozoa in carriers of t(1;11)(p36.22;q12.2).

Cumulative data obtained from two relatively large pedigrees of a unique reciprocal chromosomal translocation (RCT) t(1;11)(p36.22;q12.2) ascertained by three miscarriages (pedigree 1) and the birth of newborn with hydrocephalus and myelomeningocele (pedigree 2) were used to estimate recurrence risks for different pregnancy outcomes. Submicroscopic molecular characterization by fluorescent in situ hybridization (FISH) of RCT break points in representative carriers showed similar rearrangements in both families. Meiotic segregation patterns after sperm analysis by three-color FISH of one male carrier showed all possible outcomes resulting from 2:2 and 3:1 segregations. On the basis of empirical survival data, we suggest that only one form of chromosome imbalance resulting in monosomy 1p36.22→pter with trisomy 11q12.2→qter may be observed in progeny at birth. Segregation analysis of these pedigrees was performed by the indirect method of Stengel-Rutkowski and showed that probability rate for malformed child at birth due to an unbalanced karyotype was 3/48 (6.2±3.5%) after ascertainment correction. The risk for stillbirths/early neonatal deaths was -/48 (<1.1%) and for miscarriages was 17/48 (35.4±6.9%). However, the probability rate for children with a normal phenotype at birth was 28/48 (58.3±7.1%). The results obtained from this study may be used to determine the risks for the various pregnancy outcomes for carriers of t(1;11)(p36.22;q12.2) and can be used for genetic counseling of carriers of this rearrangement.

[Risk estimation of different pregnancy outcomes in the families of carriers of reciprocal chromosomal translocations involving chromosome 20]. / Ocena prawdopodobienstwa wystapienia róznych patologii ciazy w rodzinach nosicieli translokacji chromosomowych wzajemnych angazujacych chromosom 20.

UNLABELLED: Carriership of reciprocal chromosome translocation (RCT) in a family may be the reason for malformation at birth, stillbirth, early neonatal death, and miscarriage due to unbalanced karyotype (monosomy/trisomy). The size of chromosome segments determined by the breakpoint position, kind of chromosome involved and the carrier gender may influence the probability rate for each category of the unfavorable pregnancy outcome in the family of the carrier of a particular RCT Until now, the literature lacks reports on the risk values for particular forms of pregnancy outcomes in case of single segment imbalance, both the short (p) and the long arm (q) of chromosome 20. OBJECTIVE: The aim of the study was to evaluate individual risk rates for unbalanced offspring at birth for single segment imbalance in the form of trisomy/monosomy and a separate evaluation risk figures for different pregnancy outcomes, depending on the size of the involved chromosome segment, its origin and carrier gender in families of RCT carriers involving chromosome 20 (RCT-20). In addition, practical application of the obtained results in the family with unique RCT t(13;20)(q14.1;p11.21) carriership has been shown. MATERIAL AND METHODS: Total empirical data of 50 families (219 pregnancies) were collected from 19 pedigrees of RCT-20 carriers coming from different collections of RCT and available references. Cytogenetic studies were performed by GTG technique. The probability rates of particular type of pathology related to the total number of pregnancies after ascertainment correction have been done by segregation analysis according to the method of Stengel-Rutkowski and Stene. RESULTS: The probability rate for unbalanced offspring at birth for carriers of RCT-20p was calculated as 5.5 +/- 1.8% (9/164) (medium risk). Considering parental gender of the carrier for maternal (MAT) and paternal (PAT) carriers, the probability rate values were similar i.e. 4.8 +/- 2.3% (4/84) and 4.9 +/- 2.8% (3/61), respectively. The risk figures for stillbirth/early neonatal deaths were found as 0.6 +/- 0.6% (1/164) (low risk), but separately for MAT and PAT carriers they were: 1.2 +/- 1.2% (1/84) and < 0.8% (-/61), respectively. Risk figures for miscarriages were estimated as 28.6 +/- 3.5% (47/164) (high risk), with 32.1 +/- 5.1% (27/84) for maternal carriers and 32.7 +/- 6% (20/61) for paternal carriers. The risk figures for unbalanced offspring at birth for carriers of RCT-20q were calculated as about 2.6% (0/20) (low risk), for stillbirth/early neonatal death about 2.6% (-/20) (low risk) and for miscarriage 50 +/- 11.2% (10/20) (high risk). CONCLUSIONS: 1. The probability rates for unbalanced offspring at birth and for different categories of unfavorable outcomes show differences depending on the origin and the size of chromosome 20 segment. 2. There are no differences in the value of risk figures for particular form of pregnancy pathology in relation to carrier's gender.

[Probability rate of unbalanced offspring at birth and risk of unfavorable pregnancy outcomes in families of carriers of chromosomal reciprocal translocations involving chromosome 7]. / Ocena prawdopodobienstwa urodzenia dziecka z niezrównowafonym kariotypem oraz ryzyka wystqpienia róznych patologii ciazy w rodzinach nosicieli translokacji chromosomowych wzajemnych angazujacych chromosom 7.

INTRODUCTION: Carriership of reciprocal chromosomal translocation (RCT) may be the reason the occurrence of congenital malformations in the offspring, early neonatal death, stillbirth, and recurrent miscarriages due to unbalanced karyotype of gametes. The probability rate for individual categories of unfavorable outcomes depends on the kind of chromosome involved and is individually variable. OBJECTIVES: The aim of study was to estimate the probability rates for unbalanced offspring and to evaluate the risk for different categories of unfavorable pregnancy outcomes, depending on the size of chromosomal segment with differentiation between maternal/paternal origin of the reciprocal chromosomal translocations involving chromosome 7p (RCT-7p) and 7q (RCT-7q). In addition, the use of the obtained results has been illustrated by the example of a family with unique RCT t(7;9)(p21.3,p23). MATERIAL AND METHODS: Empirical and cytogenetic data on 341 pregnancies and offspring of 133 carriers were collected from 69 pedigrees of carriers of RCT-7p and RCT-7q at risk for a single 7 segment imbalance. The probability rates of particular form of pregnancy pathology have been calculated according to the method of Stengel-Rutkowski and Stene, including all forms of meiotic segregation and their survival rates after fertilization to term childbirth. RESULTS: The probability rates for unbalanced offspring for carriers of RCT-7p after 2:2 disjunction and adjacent-1 segregation were calculated as 5.5% +/- 2.2% (6/108); for maternal (MAT) and paternal (PAT) carriers were about < 1% (0/56) and 13.6 +/- 5.2% (6/44) (p = 0.04) respectively. Considering different segment lengths of 7p, the following values for shorter and longer segments were obtained: 23.0 +/- 11.7% (3/13) for 7p21-->pter; 3.3 +/- 3.3% (1/30) for 7p 14-->pter and 3.1 +/- 2.1% (2/65) for 7p 1-->pter The risk figures for stillbirth/earl neonatal death were estimated at 2.8 +/- 1.6% (3/108), but for miscarriage were calculated at 25.9 +/- 4.2% (28/108) for carriers RCT-7p. The probability rates for unbalanced offspring at birth for carriers of RCT-7q were calculated as 2.7 +/- 1.5% (3/111); for MAT and PAT carriers were 3.5 +/- 2.0% (3/86) and < 2.6% (0/19) respectively. Considering different segment lengths of 7q, the following values for shorter and longer segments were obtained: 6.2 +/- 6.1% (1/16) for 7q33-->qter; 5.3 +/- 3.6% (2/38) for 7q32-->qter and < 0.82% (0/57) for 7q11-->qter. The risk figures for stillbirth/early neonatal death were estimated at 9.9 +/- 2.8% (11/111), but for miscarriage were calculated at 34.2 +/-4.5% (38/111) for carriers RCT-7q. The probability estimated values for unbalanced fetuses, evaluated prenatally in the second trimester of pregnancy for carriers of RCT-7p and RCT-7q were similar i.e. 41.7 +/- 14.2% (5/12) and 46.7 +/-12.9% (7/15), respectively. CONCLUSIONS: 1. The probability rates for unbalanced offspring and the risk values for individual categories of unfavorable outcomes for carriers of RCT-7 are different and depend on the size of chromosome 7 segment involved in RCT 2. The probability rate for unbalanced offspring for paternal carriers of RCT-7p is higher than for maternal carriers (p = 0.04). 3. It is suggested that the probability rate for unbalanced offspring for maternal carriers of RCT-7q may be higher than for paternal carriers.

[Searching for Tourette's syndrome gene. Part 1. Heterogeneity of clinical phenotypes]. / W poszukiwaniu genu zespolu Gilles de la Tourette'a. Czesc 1. Róznorodnosc fenotypów klinicznych.

The French neuropsychiatrist Georges Gilles de la Tourette described in 1885 the "Maladie des Tics" which later was named after him, as Gilles de la Tourette syndrome (GTS). Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by simple and complex motor and vocal tics with multiple neuropsychiatric comorbidities. GTS is often concurrent with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). There are several clinical GTS subtypes: GTS only, GTS+OCD, and GTS+OCD+ADHD. Additional clinical aspects of the disorder include occurrence of anger episodes, anxiety and mood disorders, and learning and sleeping disturbances. The genetics of GTS is complex and remains unclear. So far, no causative candidate genes have been identified. However, segregation studies in families and twins with GTS provide strong evidence for the existence of a genetic background associated with a multifactorial mode of inheritance. Progress in studies on genome variability among patients with GTS is necessary to improve pharmacotherapeutic strategies of the disorder.

[Searching for Tourette's syndrome gene. Part 2. Patient's genome variability]. / W poszukiwaniu genu zespolu Tourette'a. Czesc 2. Zmiennosc genomu chorych.

Gilles de la Tourette syndrome (GTS) is a complex, heterozygous genetic disorder. Twenty chromosomal rearrangements (7q22-q31, 8q13-q22, and 18q22) indicating genomic regions which may be involved in the etiology of the disorder have been reported in families with GTS. Moreover, pathogenic mutations responsible for GTS were found in the SLITRK1 and the L-histidine decarboxylase (HDC) genes. The W317X mutation in the HDC gene points to a possible role for histaminergic neurotransmission in the mechanism and modulation of tic disorder. The distribution of single nucleotide polymorphisms (SNPs) was examined in at least 14 candidate genes (DRD1, DRD2, DRD3, DRD4, DAT1, MAOA, 5HTR2A, 5HTR3A, TDO2, CNR1, HLA-DRB, IL1RA, MOG, and SGCE) using a case-control genetic association analysis. Still, a lack of replicated and consistent results was observed. Recently, rare structural variants of different genes involved in neurodevelopment determined by recurrent exonic copy number variations (CNVs) have been found in a subset of patients suffering from GTS.

[Systemic sclerosis. Part 1: searching for genetic determinants]. / Twardzina ukladowa. Czesc 1: poszukiwanie genetycznych uwarunkowan.

Familial aggregation of systemic sclerosis observed in the 1970 of twenty century, the presence of karyotype instability and chromosomal mosaicism and positive associations of certain polymorphisms of genes located in specific regions of the human genome may indicate the important contribution of genetic factors in the development and progression of the disease. The purpose of this paper is to present data on genetic changes found in scleroderma. Despite the enormous progress of research it is not yet clear, which disturbances in a specific way determine onset and development of the disease and which are non-specific forms of molecular abnormalities also present in other diseases with similar clinical symptoms.

Wolf-Hirschhorn syndrome due to pure and translocation forms of monosomy 4p16.1 → pter.

The aim of this study was to obtain a quantitative definition of Wolf-Hirschhorn syndrome (WHS) through systematic phenotypic analyses in a group of six children with 4p15.32 → pter, 4p15.33 → pter, or 4p16.1 → pter monosomy (considered together as M4p16.1). These results were used for evaluation of the phenotypic effects of a double chromosome imbalance in one child with 4p16.1 → pter monosomy and additional 11q23.3 → qter trisomy. Children with pure M4p16.1 presented with a total of 227 clinical and morphological traits, of which 119 were positive in at least two of them. These traits overlap to a great extent with clinical criteria defining the WHS phenotype. Among the 103 traits identified in the child with unbalanced translocation der(4)t(4;11)(p16.1;q23.3), most clinical and developmental traits (but only 11 morphological) were found to be shared by WHS children with pure M4p16.1 and at least one reported patient with pure 11q trisomy. Forty-six traits of this child corresponded solely to those identified in at least one child with pure M4p16.1. Only five traits of the hybrid phenotype were present in at least one child with pure distal 11q trisomy but in none of the present children with pure M4p16.1. In conclusion, most of the morphological traits of the hybrid phenotype in the child with der(4)t(4;11)(p16.1;q23.3) can be attributed to the M4p16.1, whereas their overlap with those associated with pure distal 11q trisomy is less evident. Phenotype analyses based on the same systematic data acquisition may be useful in understanding the phenotypic effects of different chromosome regions in complex rearrangements. © 2011 Wiley-Liss, Inc.

Phoniatric, Audiological, Orodental and Speech Problems in a Boy with Cardio-Facio-Cutaneous Syndrome Type 3 (CFC 3) Due to a Pathogenic Variant in MAP2K1 - Case Study.

Cardio-facio-cutaneous syndrome 3 (CFC3) due to variants in MAP2K1 is a rare genetic disorder manifested mainly by short stature, facial dysmorphism, abnormalities of the cardiovascular system, skin changes, and intellectual disability. The aim of the study is the evaluation of the occurrence of pathological changes in the upper respiratory tract, orthodontic disorders, as well as voice, speech and hearing abnormalities in an 11-year-old boy with CFC3 syndrome. The lack of detailed diagnostics of speech, voice and hearing disorders, as well as the degree of their severity was an inspiration to undertake research in this field. Pathological changes in face, oral cavity, upper respiratory tract (nose, nasopharynx, larynx), and hearing organ, as well as voice and speech quality, were assessed in an 11-year-old boy with CFC3 syndrome. Pathologies of the upper respiratory tract (adenoid hypertrophy, narrowing of the nasal passages) and laryngeal asymmetry were found without significant changes in voice quality in the acoustic examination, except for the voice timbre change confirmed in narrowband spectrography. Complex audiological assessment confirmed the existence of bilateral sensorineural hearing loss. Speech pathology assessment revealed abnormalities in the structure of articulation organ, its decreased motor efficiency, imprecision, reduced coordination, as well as the presence of autistic features. Exome sequencing showed the heterozygous variant c.371C>T (p.Pro124Leu) in the MAP2K1 gene, previously described as pathogenic, thus supporting a causative relevance. Phoniatric, audiological, orodental and speech problems should be considered as features of cardio-facio-cutaneous syndrome type 3 (CFC 3) phenotype due to a pathogenic variant in MAP2K1.

L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth type 4C4 (CMT4C4) phenotype.

Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype-genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected "regional" S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.

[Genetic counseling in osteodystrophy Albright syndrome. Part I. Phenotypic diagnosis and pedigree analysis]. / Poradnictwo genetyczne w zespole osteodystrofii Albrighta, czyli rzekomej niedoczynnosci przytarczyc. Cz. I. Diagnoza fenotypowa i analiza rodowodowa.

In this article we describe problems of genetic counseling with features of morphological phenotype, biochemical and molecular changes observed in osteodystrophy Albright syndrome, inherited autosomal dominant condition.

[Genetic counseling in osteodystrophy Albright's syndrome. Part II. GNAS1 gene and encoded protein function, genetic forecast and treatment]. / Poradnictwo genetyczne w zespole osteodystrofii Albrighta, czyli rzekomej niedoczynnosci przytarczyc. Cz. II. Gen GNAS1 i funkcje kodowanego bialka, elementy prognozy genetycznej i mozliwosci leczenia.

In this article we describe localization and structure of genes from GNAS1 cluster, which mutations are responsible for characteristic group of features described mainly as Albright's syndrome. We present the capabilities of expressions of different phenotypes depending on types of molecular changes and possibilities of genetic prognosis with problems need to be solved in interdisciplinary support.