Search

Introduction: Xia-Gibbs syndrome (OMIM 615829) is a rare developmental disorder, caused by heterozygous de novo variants in the AHDC1 gene. Hallmark features include global developmental delay, facial dysmorphisms, and behavioral problems. To date, more than 250 individuals have been diagnosed worldwide., Case Report: We report a 13-year-old female who, in association with typical features of Xia-Gibbs syndrome, presented with macrocrania, pes cavus, and conjunctival melanosis. Whole-exome sequencing identified a de novo frameshift variant, which had not been reported in the literature before., Conclusion: We summarized the main clinical and phenotypic features of patients described in the literature, and in addition, we discuss another feature found in our patient and observed in other cases described, eye asymmetry, which has never been highlighted, and suggest that it could be part of the typical clinical presentation of this condition., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)

Introduction and Methods: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers., Results: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words., Discussion: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: Synaptotagmin 1 (SYT1), the predominant SYT isoform in the central nervous system, likely acts by promoting vesicle docking, deforming the plasma membrane via Ca 2+ -dependent membrane penetration., Case Presentation: Here, we describe a 21-year-old woman harboring a novel variant in the SYT1 gene, who presents with a complex phenotype, featuring severe intellectual disability, absent speech, behavioral abnormalities, motor stereotypies, dystonic posturing of her hands, a hyperkinetic movement disorder in her childhood, infantile hypotonia, sialorrhea, mild dysmorphic features, epilepsy, peculiar EEG findings, and severe scoliosis., Discussion: Based on our case and literature review on the 22 previously described patients, we can confirm a complex neurodevelopmental disorder in which, unlike other synaptopathies, epilepsy is present in a subset of cases (including our patient: 5/23, 22%), although characteristic EEG changes are far more common (10/23, 43.5%). Our patient's age allows us to provide long-term follow-up data and thus better delineate the SYT1 -related clinical phenotype., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)

Background: SOX2 disorders are associated with anophthalmia-esophageal-genital syndrome or microphthalmia, syndromic 3 (MCOPS3- # 206900). Case Report: We describe a third fetal case with a de novo 3q26.32q26.33 deletion extending for 4.31 Mb, detected in a 15-week fetus. After legal interruption of pregnancy, at autopsy, the fetus presented bilateral microphthalmia, right cleft lip and palate, bilateral cerebral ventriculomegaly and dilated third ventricle, microcystic left lung, and intestinal malrotation. Histologically, the left lung showed congenital pulmonary airway malformation (CPAM) type 2. Retinal dysplasia was found in both eyes. Discussion/Conclusion: The human SOX2 gene (OMIM #184429) is located on chromosome 3 at position q26.3-27 and encodes a transcription factor involved in the development of the central and peripheral nervous systems, retina, and lung. In our case, the combination of cerebral, retinal, and pulmonary anomalies, not previously described, are consistent with SOX2 haploinsufficiency due to chromosomal deletion.

Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a syndromic condition or as an isolated malformation. The most common of the six genetic loci identified for this condition is correlated to SHFM1 and maps in the 7q21q22 region. SHFM1 is characterized by autosomal dominant transmission, incomplete penetrance and variable expressivity. Associated features often include hearing loss, intellectual disability/developmental delay and craniofacial abnormalities. Disruption of the DLX5/DLX6 genes, mapping within the SHFM1 locus, is now known to be responsible for the phenotype. Through SNP array, we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I); we identified a deletion in 7q21, not involving the DLX5 /6 genes, but including exons 15 and 17 of DYNC1I1 , known to act as exonic enhancers (eExons) of the DLX5 /6 genes. We further demonstrated the role of DYNC1I1 eExons in regulating DLX5 /6 expression by means of showing a reduced expression of the DLX5 /6 genes through RT-PCR in a patient-derived lymphoblastoid cell line. Furthermore, our data and a review of published cases do not support the hypothesis that DLX5 /6 are imprinted in humans. This work is an example of how the disruption of regulatory elements can be responsible for congenital malformations.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs ∗ 33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies.", Competing Interests: Declaration of interests J.R.L. has stock ownership in 23andMe and is a paid consultant for the Regeneron Genetics Center., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Congenital Stationary Night Blindness type 2 (CSNB2) and Aland island Eye Disease (AIED) associated with CACNA1F mutation demonstrate a significant phenotype overlapping. We report two cases with different clinical presentation carrying two novel mutations in CACNA1F gene. Subjects underwent a complete neurophtahlmological examination associated with structural and electrofunctional insight. Next Generation Sequencing (NGS) analysis of 31 genes previously associated with retinal dystrophy (RD) was performed. Messenger RNAs derived from probands 'peripheral blood samples were analyzed by RT-PCR and cDNA sequencing. The neuro-ophthalmological examinations revealed different clinical, structural and morphological presentations, more severe in patient 1 compared with patient 2. Molecular analysis revealed, that both patients had the hemizygous form of two novel mutations in CACNA1F gene. Patient 1 presented a duplication (c.425dupC) in exon 4, resulting in shifting of the reading frame with the insertion of a premature Stop codon. In Patient 2 variant c.5156G > C localized in the donor's splicing site of exon 43 was identified. Complementary DNA sequencing demonstrated skipping of exon 43 with a deletion of 55 amino acids that causes a frame shift with insertion of a Stop codon. These findings suggest that the effect and the localization of the mutations in the CACNA1F gene can explain different clinical phenotypes. Clinical spectrum is more severe and resembles the AIED phenotype when the mutation affects the first part of the protein, while it is more similar to CSNB2 if the mutation is localized at the end of the protein. Genetic testing results to be an essential tool to provide more accurate diagnosis and prognosis in patients with inherited retinal degenerative disorders and could help, in the future, to develop more specific therapeutic strategies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care., (© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified, MCPH1 or Microcephalin , encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression. It is also involved in DNA damage response and telomere maintenance in the nucleus. Despite numerous studies on MCPH1 function, MCPH1-affected individuals are rare and the available clinical reports are not sufficient to define the natural history of the disease. Here, we present a novel patient with congenital microcephaly, ID, language delay, short stature, and other minor features such as strabismus. magnetic resonance imaging revealed ventriculomegaly, simplified gyral pattern in the frontal lobes, and a neuronal migration defect. Genetic testing detected a homozygous deletion of exons 1-8 of MCPH1 . We compare the patients' characteristics with a list of features from MCPH1 cases described in the literature, in an effort to provide additional clues for a comprehensive definition of disease presentation and evolution.

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

The term "arthrogryposis" is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys-Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis.

Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in CEP85L , encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo-occipito-parietal regions of both hemispheres with "double-cortex" (Dobyns' 1-2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the CEP85L gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic CEP85L variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with CEP85L variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly.

One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is White-Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the POGZ gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb-a remarkable clinical feature in the first years of life-and heterozygous for a previously unreported, de novo splicing variant in POGZ . This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition.

Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is an extremely rare autosomal recessive genetic disorder caused by variants in the MED25 gene. It is characterized by severe developmental delay and variable craniofacial, neurological, ocular, and cardiac anomalies. Since 2015, through whole exome sequencing, 20 patients have been described with common clinical features and biallelic variants in MED25, leading to a better definition of the phenotype associated with BVSYS. We report two young sisters, born to consanguineous parents, presenting with intellectual disability, neurological findings, and dysmorphic features typical of BVSYS, and also with bilateral perisylvian polymicrogyria. The younger sister died at the age of 1 year without autoptic examination. Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs). This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients., (© 2020 Wiley Periodicals LLC.)

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.

Variations in genes encoding for the enzymes responsible for synthesizing the linker region of proteoglycans may result in recessive conditions known as "linkeropathies". The two phenotypes related to mutations in genes B4GALT7 and B3GALT6 (encoding for galactosyltransferase I and II respectively) are similar, characterized by short stature, hypotonia, joint hypermobility, skeletal features and a suggestive face with prominent forehead, thin soft tissue and prominent eyes. The most outstanding feature of these disorders is the combination of severe connective tissue involvement, often manifesting in newborns and infants, and skeletal dysplasia that becomes apparent during childhood. Here, we intend to more accurately define some of the clinical features of B4GALT7 and B3GALT6 -related conditions and underline the extreme hypermobility of distal joints and the soft, doughy skin on the hands and feet as features that may be useful as the first clues for a correct diagnosis., Competing Interests: All authors declare that there are no conflicts of interest concerning this work.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS., Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations., Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations., Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.

Competing Interests: The authors declare they have no potential conflict of interest to disclose.

Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals., (© 2018 Wiley Periodicals, Inc.)

Background: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician., Method: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed., Results: Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature., Conclusion: Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined., Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations., Results: Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical, and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis., Conclusion: This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.

Premature ovarian insufficiency (POI) is a clinical syndrome defined by a loss of ovarian activity before the age of 40. Its pathogenesis is still largely unknown, but increasing evidences support a genetic basis in most cases. Among these, heterozygous mutations in NOBOX, a homeobox gene encoding a transcription factor expressed specifically by oocyte and granulosa cells within the ovary, have been reported in ∼6% of women with sporadic POI. The pivotal role of NOBOX in early folliculogenesis is supported by findings in knock-out mice. Here, we report the genetic screening of 107 European women with idiopathic POI, recruited in various settings, and the molecular and functional characterization of the identified variants to evaluate their involvement in POI onset. Specifically, we report the identification of two novel and two recurrent heterozygous NOBOX variants in 7 out of 107 patients, with a prevalence of 6.5% (upper 95% confidence limit of 11.17%). Furthermore, immunolocalization, Western Blot and transcriptional assays conducted in either HEK293T or CHO cells revealed that all the studied variants (p.R44L, p.G91W, p.G111R, p.G152R, p.K273*, p.R449* and p.D452N) display variable degrees of functional impairment, including defects in transcriptional activity, autophagosomal degradation, nuclear localization or protein instability. Several variants conserve the ability to interact with FOXL2 in intracellular aggregates. Their inability to sustain gene expression, together with their likely aberrant effects on protein stability and degradation, make the identified NOBOX mutations a plausible cause of POI onset., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.

Unlabelled: Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients., Conclusion: Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity., What Is Known: • The clinical and radiological signs of the disease in children older than 7-8 years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.

Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation., (© 2015 Wiley Periodicals, Inc.)

Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Creatine deficiency syndrome due to mutations in X-linked SLC6A8 gene results in nonspecific intellectual disability (ID). Diagnosis cannot be established on clinical grounds and is often based on the assessment of brain creatine levels by magnetic resonance spectroscopy (MRS). Considering high costs of MRS and necessity of sedation, this technique cannot be used as a first level-screening test. Likewise, gene test analysis is time consuming and not easily accessible to all laboratories. In this article feasibility of urine analysis (creatine/creatinine (Cr/Crn) ratio) performed by nuclear magnetic resonance (NMR) as a first level-screening test is explored. Before running a systematic selection of cases a preliminary study for further molecular analysis is shown. NMR urine spectra (n = 1,347) of male patients with an ID without a clinically recognizable syndrome were measured. On the basis of abnormal Cr/Crn ratio, three patients with the highest values were selected for molecular analysis. A confirmatory second urine test was positive in two patients and diagnosis was further confirmed by a decreased brain creatine level and by SLC6A8 gene analysis. A de novo mutation was identified in one. Another patient inherited a novel mutation from the mother who also has a mild ID. A repeat urine test was negative in the third patient and accordingly creatine level in the brain and SLC6A8 gene analysis both gave a normal result. We conclude that Cr/Crn ratio measured by NMR for male patients represents a rapid and useful first level screening test preceding molecular analysis., (Copyright © 2011 Wiley-Liss, Inc.)

MECP2 mutations are responsible for two different phenotypes in females, classical Rett syndrome and the milder Zappella variant (Z-RTT). We investigated whether copy number variants (CNVs) may modulate the phenotype by comparison of array-CGH data from two discordant pairs of sisters and four additional discordant pairs of unrelated girls matched by mutation type. We also searched for potential MeCP2 targets within CNVs by chromatin immunopreceipitation microarray (ChIP-chip) analysis. We did not identify one major common gene/region, suggesting that modifiers may be complex and variable between cases. However, we detected CNVs correlating with disease severity that contain candidate modifiers. CROCC (1p36.13) is a potential MeCP2 target, in which a duplication in a Z-RTT and a deletion in a classic patient were observed. CROCC encodes a structural component of ciliary motility that is required for correct brain development. CFHR1 and CFHR3, on 1q31.3, may be involved in the regulation of complement during synapse elimination, and were found to be deleted in a Z-RTT but duplicated in two classic patients. The duplication of 10q11.22, present in two Z-RTT patients, includes GPRIN2, a regulator of neurite outgrowth and PPYR1, involved in energy homeostasis. Functional analyses are necessary to confirm candidates and to define targets for future therapies.

During the last few years, an increasing number of microdeletion/microduplication syndromes have been delineated. This rapid evolution is mainly due to the availability of microarray technology as a routine diagnostic tool. Microdeletions of the 21q22.11q22.12 region encompassing the RUNX1 gene have been reported in nine patients presenting with syndromic thrombocytopenia and mental retardation. RUNX1 gene is responsible for an autosomal dominant platelet disorder with predisposition to acute myelogenous leukemia. We report on three novel patients with an overlapping "de novo" interstitial deletion involving the band 21q22 characterized by array-CGH. All our patients presented with severe developmental delay, dysmorphic features, behavioral problems, and thrombocytopenia. Comparing the clinical features of our patients with the overlapping ones already reported two potential phenotypes related to 21q22 microdeletion including RUNX1 were highlighted: thrombocytopenia with +/- mild dysmorphic features and syndromic thrombocytopenia with growth and developmental delay., ((c) 2010 Wiley-Liss, Inc.)

21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia, an autosomal recessive disorder characterized by impaired synthesis of cortisol from cholesterol by the adrenal cortex. Subclinical involvement of brain white matter has been reported in subjects with congenital adrenal hyperplasia. Here we report a woman with a genetically assessed classic congenital adrenal hyperplasia and brain white matter abnormalities. Both the carrier parents also showed signs of leucoencephalopathy. Common causes of leukoencephalopathy were excluded by appropriate analyses. Our observation suggests that white matter anomalies may also be present in carriers of a mutation in the CYP21 gene. We therefore suggest performing CYP21 gene analysis in subjects with brain MRI evidence of white matter abnormalities that cannot otherwise be explained., (Copyright 2009. Published by Elsevier B.V.)

We report a patient with mental retardation, epilepsy, overgrowth, delayed bone age, peculiar facial features, corpus callosum hypoplasia, enlarged cisterna magna and right cerebellar hypoplasia. Array-CGH analysis revealed the presence of a de novo 3.2 Mb interstitial deletion of the long arm of chromosome 7 involving bands q22.2-q22.3. The rearrangement includes 15 genes and encompasses a genomic region that represents a site of frequent loss of heterozygosity in myeloid malignancies. Four genes are implicated in the control of cell cycle: SRPK2, MLL5, RINT1 and LHFPL3. Haploinsufficiency of these genes might therefore be associated with overgrowth and could confer susceptibility to cancers or other tumours, so that attention to this possibility would be appropriate during regular medical review. In conclusion, array-CGH analysis should be performed in patients with overgrowth where the known causes have already been excluded, because some still unclassified overgrowth syndromes may be caused by subtle genomic imbalances., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Tibial muscular dystrophy (TMD) or Udd myopathy is an autosomal dominant distal myopathy with late onset, at first described in the Finnish population. We report here the first Italian cases of TTN mutated titinopathy. The proband, a 60 year-old female, had the first muscular signs at the age of 59 years, with difficulty in walking and right foot drop. Muscle imaging showed selective fatty degenerative change in the anterior compartment of leg muscles. Her 67 year-old brother, started to show muscle weakness, pain at lower limbs and hypertrophy of calf muscles at the age of 66 years. Their mother began to show foot drop and impaired walking from the age of 60 years. Other relatives are reported to be affected in a similar way. Because the phenotype appeared compatible with TMD, we analyzed the TTN gene in the DNA of the proband and we identified a heterozygous mutation 293326A>C. This mutation is also present in the brother and in the other affected individuals of the same family. The mutation predicts a His33378Pro change located next to the previously known Belgian TMD mutation. The mutation was not found in 100 Italian control DNA samples. Then, since the introduction of a proline in the last domain of titin was previously known to cause TMD in French families, we can conclude that this missense mutation is the obvious pathogenetic mutation in the affected patients. No other disease causing mutations in the TTN gene have so far been reported in the Italian population.

Background: Rett syndrome is a severe neurodevelopmental disorder affecting almost exclusively females. Among Rett clinical variants, the early-onset seizure variant describes girls with early onset epilepsy and it is caused by mutations in CDKL5., Methods: Four previously reported girls and five new cases with CDKL5 mutation, ranging from 14 months to 13 years, were evaluated by two clinical geneticists, classified using a severity score system based on the evaluation of 22 different clinical signs and compared with 128 classic Rett and 25 Zappella variant MECP2-mutated patients, evaluated by the same clinical geneticists. Clinical features were compared with previously described CDKL5 mutated patients. Both the statistical and the descriptive approach have been used to delineate clinical diagnostic criteria., Results: All girls present epilepsy with onset varying from 10 days to 3 months. Patients may present different type of seizures both at onset and during the whole course of the disease; multiple seizure types may also occur in the same individual. After treatment with antiepileptic drugs patients may experience a short seizure-free period but epilepsy progressively relapses. Typical stereotypic hand movements severely affecting the ability to grasp are present. Psychomotor development is severely impaired. In the majority of cases head circumference is within the normal range both at birth and at the time of clinical examination., Conclusion: For the practical clinical approach we propose to use six necessary and eight supportive diagnostic criteria. Epilepsy with onset between the first week and 5 months of life, hand stereotypies, as well as severe hypotonia, are included among the necessary criteria., (Copyright 2009 Elsevier B.V. All rights reserved.)

Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

We describe a de novo 3q27.3q29 deletion in a 2.5-year-old female patient with developmental and growth delay, dysmorphic facial features, mild tricuspid valve dysplasia, bifid thumb, clinodactyly of the 2nd toe bilaterally and scoliosis. The deletion overlaps for about 1Mb with the 1.6Mb region commonly deleted in patients with 3q29 microdeletion syndrome. The phenotype of the two syndromes is not completely overlapping, though the most important clinical features, such as mental retardation and microcephaly, occur in both. This suggests that the deletion in our patient causes a distinct clinical phenotype, not described previously. In the deleted region there are 47 annotated genes. Among them, seven are of particular interest for correlation with clinical features of the patient. Two genes, OPA1 and CCDC50, responsible for autosomal dominant optic atrophy and deafness, respectively, may be important for the correct follow-up of the patient.

The introduction of array-CGH analysis is allowing the identification of novel genomic disorders. However, this new high-resolution technique is also opening novel diagnostic challenges when inherited private CNVs of unclear clinical significance are found. Oligo array-CGH analysis of 84 patients with mild to severe mental retardation associated with multiple congenital anomalies revealed 10 private CNVs inherited from a healthy parent. Three were deletions (7q31, 14q21.1, Xq25) and seven duplications (12p11.22, 12q21.31, 13q31.1, 17q12, Xp22.31, Xq28) ranging between 0.1 and 3.8Mb. Six rearrangements were not polymorphic. Four overlapped polymorphic regions to the extent of 10-61%. In one case the size was different between the proband and the healthy relative. Three small rearrangements were gene deserts. The remaining seven had a mean gene content of five (ranging from 1 to 18). None of the rearranged genes is known to be imprinted. Three disease-genes were found in three different cases: KAL1 in dupXp22.31, STS in another dupXp22.31 and TCF2 in dup17q12. The patient carrying the last duplication presents sex reversal, Peters' anomaly and renal cysts and the duplication is located 4Mb away from the HSD17B1 gene, coding a key enzyme of testosterone biosynthesis. Considering the overlap with polymorphic regions, size-identity within the family, gene content, kind of rearrangement and size of rearrangement we suggest that at least in five cases the relationship to the phenotype has not to be excluded. We recommend to maintain caution when asserting that chromosomal abnormalities inherited from a healthy parent are benign. A more complex mechanism may in fact be involved, such as a concurrent variation in the other allele or in another chromosome that influences the phenotype.

Rett syndrome is a severe neurodevelopmental disease caused by mutations in the X-linked gene encoding for the methyl-CpG-binding protein MeCP2. Here, we report the identification of FOXG1-truncating mutations in two patients affected by the congenital variant of Rett syndrome. FOXG1 encodes a brain-specific transcriptional repressor that is essential for early development of the telencephalon. Molecular analysis revealed that Foxg1 might also share common molecular mechanisms with MeCP2 during neuronal development, exhibiting partially overlapping expression domain in postnatal cortex and neuronal subnuclear localization.