Papers by Livia Garavelli
Genes, Oct 12, 2019
Variations in genes encoding for the enzymes responsible for synthesizing the linker region of pr... more 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.
Journal of Medical Genetics, Aug 16, 2023
Background KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrod... more Background KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. Methods CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, ⇒ KBG syndrome is a well-characterised neurodevelopmental disorder caused by ANKRD11 haploinsufficiency, but the neuroimaging and skeletal features remain poorly defined and often overlooked. ⇒ Systematic evaluation of diagnostic imaging in a large cohort of patients highlighted the deep phenotype and natural history of KBG-related brain, spine and skeletal abnormalities, and allowed us to define their prevalence. ⇒ This qualitative and quantitative description of the radiological and neuroradiological features will aid clinicians to better evaluate and manage individuals with KBG syndrome. ⇒ Our data provide a reference for future research on animal models concerning the cerebral and skeletal consequences of ANKRD11 variants.
The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder
The American Journal of Human Genetics
Genes
Pathogenic variants in RASA1 are typically associated with a clinical condition called “capillary... more Pathogenic variants in RASA1 are typically associated with a clinical condition called “capillary malformation-arteriovenous malformation” (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in the central nervous system, spine and skin. Although CM-AVM syndrome has been widely described in the literature, only 21 cases with prenatal onset of clinical features have been reported thus far. Here, we report four pediatric cases of molecularly confirmed CM-AVM syndrome which manifested during the prenatal period. Polyhydramnios, non-immune hydrops fetalis and chylothorax are only a few possible aspects of this condition, but a correct interpretation of these prenatal signs is essential due to the possible fatal consequences of unrecognized encephalic and thoracoabdominal deep vascular malformations in newborns and in fa...
Genes
Lissencephaly describes a group of conditions characterized by the absence of normal cerebral con... more 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 var...
American Journal of Medical Genetics Part A
Wiedemann–Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous ... more 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 anom...
Genes, 2022
Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gr... more 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.
Genes, 2021
One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed... more 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 adduc...
Il progetto pilota di Registro Italiano delle Neurofibromatosi
Genes, 2021
We report on two siblings suffering from different pathogenic conditions, born to consanguineous ... more We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targe...
A monoallelicSEC23AvariantE599Kassociated withcranio‐lenticulo‐suturaldysplasia
American Journal of Medical Genetics Part A, 2021
Cranio‐lenticulo‐sutural dysplasia (CLSD; MIM 607812) is a rare or underdiagnosed condition, as o... more Cranio‐lenticulo‐sutural dysplasia (CLSD; MIM 607812) is a rare or underdiagnosed condition, as only two families have been reported. The original family (Boyadjiev et al.,Human Genetics, 2003, 113, 1–9 and Boyadjiev et al.,Nature Genetics, 2006, 38, 1192–1197) showed recessive inheritance of the condition with a biallelicSEC23Amissense variant in affected individuals. In contrast, another child with sporadic CLSD had a monoallelicSEC23Avariant inherited from the reportedly unaffected father (Boyadjiev et al.,Clinical Genetics, 2011, 80, 169–176), raising questions on possible digenism. Here, we report a 2‐month‐old boy seen because of large fontanels with wide cranial sutures, a large forehead, hypertelorism, a thin nose, a high arched palate, and micrognathia. His mother was clinically unremarkable, while his father had a history of large fontanels in infancy who had closed only around age 10 years; he also had a large forehead, hypertelorism, a thin, beaked nose and was operated ...
Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygo... more Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe intellectual disability, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies, congenital heart defects, agenesis of the corpus callosum, and eye defects. To date, a clear description of the physical development of MWS patients does not exist. The aim of the study is to provide up-to-date growth charts specific for infants and children with MWS. The charts for males and females aged from 0 to 16 years were constructed using a total of 2,865 measurements of 99 MWS patients, of different ancestries. The data were collected through extensive collaboration with the Italian MWS association (AIMW) and the MWS Foundation. To model the growth charts, the GAMLSS package for the R statistical program was used. Height, weight, body mass index (BMI) and head cir...
Prominent and elongated coccyx, a new manifestation of KBG syndrome associated with novel mutation in ANKRD11
American Journal of Medical Genetics Part A, 2018
KBG syndrome is characterized by short stature, distinctive facial features, and developmental/co... more KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat‐containing cofactors. After the advent of whole exome sequencing, the number of clinical reports with KBG diagnosis has increased, leading to a revision of the phenotypic spectrum associated with this syndrome. Here, we report a female child showing clinical features of the KBG syndrome in addition to a caudal appendage at the coccyx with prominent skin fold and a peculiar calcaneus malformation. Exons and exon–intron junctions targeted resequencing of SH3PXD2B and MASP1 genes, known to be associated with prominent coccyx, gave negative outcome, whereas sequencing of ANKRD11 whose mutations matched the KBG phenotype of the proband showed a de novo heterozygous frameshift variant c.4528_4529delCC in exon 9 of ANKRD11. This report contributes to expand the knowledge of the clinical features of KBG syndrome and h...
Complex cranio-vertebral malformation: disruption sequence or iniencephaly?
Clinical Dysmorphology, 2018
Clinical Genetics Unit, Obstetric and Pediatric Department, Children Neuropsychiatry Unit, Neuror... more Clinical Genetics Unit, Obstetric and Pediatric Department, Children Neuropsychiatry Unit, Neuroradiology Unit, Azienda Unità Sanitaria Locale di Reggio Emilia IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplantation, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy and Department of Pediatrics, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland Correspondence to Marzia Pollazzon, MD, Clinical Genetics Unit, Obstetric and Pediatric Department, Azienda Unità Sanitaria Locale di Reggio Emilia IRCCS Arcispedale S. Maria Nuova, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy Tel: + 39 052 229 5462; fax: + 39 052 229 5909; e-mail: [email protected]
Van Maldergem syndrome and Hennekam syndrome: Further delineation of allelic phenotypes
American Journal of Medical Genetics Part A, 2018
Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n... more 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.
Italian Journal of Pediatrics, 2018
Background: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach ... more 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.
Genetics in medicine : official journal of the American College of Medical Genetics, Sep 4, 2018
PurposeMowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalie... more PurposeMowat-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.MethodsIn 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.ResultsAll 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, w...
World journal of gastroenterology, Jan 28, 2017
The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still large... more The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several...
Genetics in Medicine, 2016
Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, mo... more 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 genotypephenotype 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. This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.
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Papers by Livia Garavelli