Publications by authors named "Orsetta Zuffardi"

204 Publications

Prenatal Noninvasive Trio-WES in a Case of Pregnancy-Related Liver Disorder.

Diagnostics (Basel) 2021 Oct 14;11(10). Epub 2021 Oct 14.

Medical Genetics Unit, Department of Medical Sciences and Public Health, University of Cagliari, 09126 Cagliari, Italy.

Liver disease in pregnancy may present as an acute condition related to the gestational period, characterized by pruritus, jaundice, and abnormal liver function. The disease may be misdiagnosed with other liver diseases, some of which may have consequences for fetal health. It is therefore advisable to implement rapid diagnostic strategies to provide information for the management of pregnancy in these conditions. We report the case of a healthy woman with a twin pregnancy from homologous in vitro fertilization (IVF), who in the third trimester presented jaundice and malaise. Biochemical investigations and liver hyperechogenicity raised the suspicion of acute fatty liver disease of pregnancy (AFLP). Non-invasive prenatal whole-exome sequencing (WES) in the trio identified the Phe305Ile heterozygous variant in the gene. Considering the twin pregnancy, the percentage of the variant versus the wild allele was of 31%, suggesting heterozygosity present in the mother alone. This analysis showed that the mother was affected by benign recurrent intrahepatic cholestasis of pregnancy (ICP1: # 147480) and indicated the opportunity to anticipate childbirth to avoid worsening of the mother's health. WES after the birth of the twins confirmed the molecular data.
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http://dx.doi.org/10.3390/diagnostics11101904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534548PMC
October 2021

NRF1 association with AUTS2-Polycomb mediates specific gene activation in the brain.

Mol Cell 2021 Nov 11;81(22):4663-4676.e8. Epub 2021 Oct 11.

Department of Biochemistry and Molecular Pharmacology, New York University Langone School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address:

The heterogeneous family of complexes comprising Polycomb repressive complex 1 (PRC1) is instrumental for establishing facultative heterochromatin that is repressive to transcription. However, two PRC1 species, ncPRC1.3 and ncPRC1.5, are known to comprise novel components, AUTS2, P300, and CK2, that convert this repressive function to that of transcription activation. Here, we report that individuals harboring mutations in the HX repeat domain of AUTS2 exhibit defects in AUTS2 and P300 interaction as well as a developmental disorder reflective of Rubinstein-Taybi syndrome, which is mainly associated with a heterozygous pathogenic variant in CREBBP/EP300. Moreover, the absence of AUTS2 or mutation in its HX repeat domain gives rise to misregulation of a subset of developmental genes and curtails motor neuron differentiation of mouse embryonic stem cells. The transcription factor nuclear respiratory factor 1 (NRF1) has a novel and integral role in this neurodevelopmental process, being required for ncPRC1.3 recruitment to chromatin.
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http://dx.doi.org/10.1016/j.molcel.2021.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604784PMC
November 2021

Posterior Lissencephaly Associated with Subcortical Band Heterotopia Due to a Variation in the Gene: A Case Report and Refining of the Phenotypic Spectrum.

Genes (Basel) 2021 08 5;12(8). Epub 2021 Aug 5.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

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 , 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 gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic 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 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.
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http://dx.doi.org/10.3390/genes12081208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391275PMC
August 2021

Adducted Thumb and Peripheral Polyneuropathy: Diagnostic Supports in Suspecting White-Sutton Syndrome: Case Report and Review of the Literature.

Genes (Basel) 2021 06 22;12(7). Epub 2021 Jun 22.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

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 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 . 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.
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http://dx.doi.org/10.3390/genes12070950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303405PMC
June 2021

Whole Exome Sequencing Is the Minimal Technological Approach in Probands Born to Consanguineous Couples.

Genes (Basel) 2021 06 24;12(7). Epub 2021 Jun 24.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

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 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the 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 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 targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.
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http://dx.doi.org/10.3390/genes12070962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303193PMC
June 2021

Clinical Manifestations in a Girl with NAA10-Related Syndrome and Genotype-Phenotype Correlation in Females.

Genes (Basel) 2021 06 10;12(6). Epub 2021 Jun 10.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy.

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the gene have been described. After the advent of whole exome sequencing, many variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype-phenotype correlation in females with -related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals.
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http://dx.doi.org/10.3390/genes12060900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230408PMC
June 2021

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

Seizure 2021 May 30;88:60-72. Epub 2021 Mar 30.

Maternal and Pediatric Department, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio "Giovanni Paolo II", Viale Padre Pio, snc, San Giovanni Rotondo (FG) 71013, Italy.

Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.

Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".

Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.

Conclusion: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.
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http://dx.doi.org/10.1016/j.seizure.2021.03.025DOI Listing
May 2021

RB1CC1 duplication and aberrant overexpression in a patient with schizophrenia: further phenotype delineation and proposal of a pathogenetic mechanism.

Mol Genet Genomic Med 2021 01 19;9(1):e1561. Epub 2020 Dec 19.

Unit of Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.

Background: Copy number variants in coding and noncoding genomic regions have been implicated as risk factor for schizophrenia (SCZ). Rare duplications of the RB1CC1 gene were found enriched in SCZ patients. Considering that the effect of such duplications on RB1CC1 expression has never been evaluated and partial gene duplications of RB1CC1 have also been reported in SCZ patients, it is unclear whether the pathogenesis is mediated by haploinsufficiency rather than genuine overexpression of the gene.

Methods And Results: We studied a patient with schizophrenia, suicidality, and obesity, who carried a de novo RB1CC1 complete duplication, as assessed by high-resolution array-CGH. Molecular breakpoint cloning allowed to identify nonhomologous end joining (NHEJ) as driving mechanism in this rearrangement. On the contrary, trio-based whole-exome sequencing excluded other potential causative variants related to the phenotype. Functional assays showed significant overexpression of RB1CC1 in the peripheral blood lymphocytes of the proband compared to control subjects, suggesting overdosage as leading mechanism in SCZ pathophysiology.

Conclusion: We hypothesized a pathogenetic model that might explain the correlation between RB1CC1 overexpression and schizophrenia by altering different cell signaling pathways, including autophagy, a promising therapeutic target for schizophrenic patients.
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http://dx.doi.org/10.1002/mgg3.1561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963413PMC
January 2021

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Hum Genet 2021 Apr 18;140(4):625-647. Epub 2020 Dec 18.

Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.
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http://dx.doi.org/10.1007/s00439-020-02231-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981314PMC
April 2021

Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome.

Eur J Med Genet 2021 Jan 12;64(1):104099. Epub 2020 Nov 12.

Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Spontaneous cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults, whose genetic susceptibility factors are still largely unknown. Nevertheless, subtle ultrastructural connective tissue alterations (especially in the collagen fibril morphology) are recognized in a large proportion of CeAD patients, in which recent genetic investigations reported an enrichment of variants in genes associated with known connective tissue disorders. In this regard, COL5A1 variants have been reported in a small subset of CeAD patients, with or without classical Ehlers-Danlos syndrome (cEDS) features. We investigated a 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS. Whole-exome sequencing identified two COL5A1 missense variants in trans configuration: NM_000093.5:c.[1588G>A];[4135C>T], NP_000084.3:p.[(Gly530Ser)];[(Pro1379Ser)]. Functional assays demonstrated a significant decrease of collagen α1(V) chain expression in both heterozygous parents compared to control cells, and an additive effect of these two variants in the proband. Interestingly, both parents manifested very subtle EDS signs, such as atrophic scars, recurrent bone fractures, colonic diverticulosis, varicose veins, and osteoarthritis. Our findings emphasize the involvement of COL5A1 in the predisposition to vascular phenotypes and provide novel insights on the c.1588G>A variant, whose functional significance has not been definitely established. In fact, it was previously reported as both "disease modifying", and as a biallelic causative mutation (with heterozygous individuals showing subtle clinical signs of cEDS). We speculated that the c.1588G>A variant might lead to overt phenotype in combination with additional genetic "hits" lowering the collagen α1(V) chain expression below a hypothetical disease threshold.
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http://dx.doi.org/10.1016/j.ejmg.2020.104099DOI Listing
January 2021

FANCA, TP53, and del(5q)/RPS14 alterations in a patient with T-cell non-Hodgkin lymphoma and concomitant Fanconi anemia and Li-Fraumeni syndrome.

Cancer Genet 2021 08 31;256-257:179-183. Epub 2020 Oct 31.

Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy.

We traced the neoplastic history (from 5 to 11 years of age) of a child with concomitant Fanconi anemia and Li-Fraumeni syndrome. Interestingly, the patient developed a highly malignant T-cell non-Hodgkin lymphoma (NHL), which does not represent the typical tumor type in the two aforementioned syndromes, presumably due to the underlying genomic instability. By using a combination of molecular and immunohistochemical approaches, we characterized the accumulation of multiple genetic alterations in a single patient, with both germline (parentally inherited biallelic FANCA variants and a likely de novo nonsense variant in TP53) and somatic (TP53 loss of heterozygosity and 5q interstitial deletion) contributions. Our findings support the interplay of TP53 and FANC genes in DNA damage response pathways and further highlight the genetic heterogeneity of lymphomas as well as the contribution of genomic instability to lymphomagenesis.
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http://dx.doi.org/10.1016/j.cancergen.2020.10.003DOI Listing
August 2021

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

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.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding.

Neurogenetics 2021 03 20;22(1):19-25. Epub 2020 Aug 20.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

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.
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http://dx.doi.org/10.1007/s10048-020-00625-2DOI Listing
March 2021

Disseminated Infection in a Child with Complete Interferon-γ Receptor 1 Deficiency due to Compound Heterozygosis of for a Subpolymorphic Copy Number Variation and a Novel Splice-Site Variant.

J Pediatr Genet 2020 Sep 4;9(3):186-192. Epub 2019 Nov 4.

Pediatric Hematology-Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.

Complete interferon-γ receptor 1 deficiency is a monogenic primary immunodeficiency caused by germline defects, with autosomal dominant or recessive inheritance, which results in invasive mycobacterial diseases with varying degrees of severity. Most of the autosomal recessive mutations are homozygous loss-of-function single-nucleotide variants, whereas large genomic deletions and compound heterozygosity have been very rarely reported. Herein we describe the clinical presentation, diagnosis, and successful treatment with hematopoietic stem cell transplantation of a child with disseminated infection due to compound heterozygosity for a subpolymorphic copy number variation and a novel splice-site variant.
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http://dx.doi.org/10.1055/s-0039-1700803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375849PMC
September 2020

Characterization of a novel loss-of-function variant in TDP2 in two adult patients with spinocerebellar ataxia autosomal recessive 23 (SCAR23).

J Hum Genet 2020 Dec 10;65(12):1135-1141. Epub 2020 Jul 10.

Medical Genetics Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.
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http://dx.doi.org/10.1038/s10038-020-0800-4DOI Listing
December 2020

Targeted next-generation sequencing identifies the disruption of the and genes in a patient carrying a de novo t(1;22)(q43;q13.3) associated with signs of Phelan-McDermid syndrome.

Mol Cytogenet 2020 11;13:22. Epub 2020 Jun 11.

Oasi Research Institute-IRCCS, Troina, Italy.

Background: It has been known for more than 30 years that balanced translocations, especially if de novo, can associate with congenital malformations and / or neurodevelopmental disorders, following the disruption of a disease gene or its cis-regulatory elements at one or both breakpoints.

Case Presentation: We describe a 10-year-old girl with a non-specific neurodevelopmental disorder characterized by moderate intellectual disability (ID), gross motor clumsiness, social and communication deficits. She carries a de novo reciprocal translocation between chromosomes 1q43 and 22q13.3, the latter suggesting the involvement of Indeed, its haploinsufficiency associates with Phelan-McDermid Syndrome, whose main symptoms are characterized by global developmental delay and absent or severely delayed expressive speech. A deep molecular approach, including next-generation sequencing of locus, allowed demonstrating the breakage of and on the derivative chromosomes 1 and 22 respectively, and the formation of two fusion genes and with concomitant cryptic deletion of 3.6 and 4.1 kilobases at translocation junction of both derivatives chromosomes 22 and 1, respectively.

Conclusions: Although the interruption of accounts for the patient's psychomotor retardation and autism-like behavior, we do not exclude that the interruption of may also have a role on her disorder, or result in further pathogenicity in the future. Indeed, that has a well-established role in the etiology of two autosomal dominant adulthood cardiac disorders (#600996 and #604772) is also expressed in the brain (cerebellum, hippocampus, and cerebral cortex) and about half of mutation carriers present late onset primary generalized epilepsy without cardiac arrhythmogenic disorders. Moreover, variants have also been sporadically reported in individuals with early onset schizophrenia or ID, and its constraint values suggest intolerance to loss-of-function. This study not only confirms the usefulness of the molecular mapping of de novo balanced rearrangements in symptomatic individuals, but also underscores the need for long-term clinical evaluation of the patients, for better evaluating the pathogenicity of the chromosomal breakpoints.
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http://dx.doi.org/10.1186/s13039-020-00490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291734PMC
June 2020

Noninvasive prenatal diagnosis in a family at risk for Fraser syndrome.

Prenat Diagn 2020 06 20;40(7):905-908. Epub 2020 Apr 20.

Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.

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http://dx.doi.org/10.1002/pd.5700DOI Listing
June 2020

A novel de novo partial xq duplication in a girl with short stature, nonverbal learning disability and diminished ovarian reserve - effect of growth hormone treatment and fertility preservation strategies: a case report and up-to-date review.

Int J Pediatr Endocrinol 2020 9;2020. Epub 2020 Jan 9.

6Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, Division of Paediatrics, University of Verona, Verona, Italy.

Background: Xq duplication is a rare condition with a very variable phenotype, which could mimic other genetic syndromes involving the long arm of chromosome X. Sometimes short stature and diminished ovarian reserve (DOR) may be present. Treatments with rGH (Recombinant growth Hormon) or with fertility preservation strategies have not been previously described.

Case Presentation: We present the case of a female with a novel de novo Xq partial duplication (karyotype: 46,Xder(X)(qter→q21.31::pter→qter) confirmed by array-CGH analysis. She presented with short stature, Nonverbal Learning Disability, developmental delay during childhood, severe scoliosis, spontaneous onset of menarche and irregular menstrual cycles. AMH (Anti-Müllerian Hormone) allowed detection of a preserved but severely diminished ovarian reserve with a POI (Premature Ovarian insufficiency) onset risk. She was effectively subjected to fertility preservation strategies and rGH therapy. We also reviewed other published cases with Xq duplication, reporting the main clinics characteristics and any adopted treatment.

Conclusions: rGH treatment and cryopreservation in a multidisciplinary approach are good therapeutic strategies for Xq duplication syndrome with short stature and premature ovarian failure.
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http://dx.doi.org/10.1186/s13633-019-0071-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953468PMC
January 2020

Alazami syndrome: the first case of papillary thyroid carcinoma.

J Hum Genet 2020 Jan 28;65(2):133-141. Epub 2019 Oct 28.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

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.
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http://dx.doi.org/10.1038/s10038-019-0682-5DOI Listing
January 2020

Phenotypic Expansion in Nasu-Hakola Disease: Immunological Findings in Three Patients and Proposal of a Unifying Pathogenic Hypothesis.

Front Immunol 2019 23;10:1685. Epub 2019 Jul 23.

Unit of Medical Genetics, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder characterized by progressive presenile dementia and bone cysts, caused by variants in either or . Despite the well-researched role of TREM2 and TYROBP/DAP12 in immunity, immunological phenotypes have never been reported in NHD patients. We initially diagnosed an Italian patient, using whole exome sequencing, with classical NHD clinical sequelae who additionally showed a decrease in NK cells and autoimmunity features underlined by the presence of autoantibodies. Based on this finding, we retrospectively explored the immunophenotype in another two NHD patients, in whom a low NK cell count and positive autoantibody serology were recorded. Accordingly, mice show abnormal levels of circulating proinflammatory cytokines and the dysfunction of immune cells, whereas knockout mice for , encoding the adapter for TREM2, exhibit increased levels of autoantibodies and defective NK cell activity. Our findings tend to redefine NHD as a multisystem "immunological" disease, considering that osteoclasts are derived from the fusion of mononuclear myeloid precursors, whereas neurological anomalies in NHD are directly caused by microglia dysfunction.
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http://dx.doi.org/10.3389/fimmu.2019.01685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664049PMC
November 2020

Hypomorphic Variants in Congenital Lymphatic Dysplasia Cause Shape and Hydration Alterations of Red Blood Cells.

Front Physiol 2019 15;10:258. Epub 2019 Mar 15.

Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.

PIEZO1 is a cation channel activated by mechanical force. It plays an important physiological role in several biological processes such as cardiovascular, renal, endothelial and hematopoietic systems. Two different diseases are associated with alteration in the DNA sequence of : (i) dehydrated hereditary stomatocytosis (DHS1, #194380), an autosomal dominant hemolytic anemia caused by gain-of-function mutations; (ii) lymphatic dysplasia with non-immune fetal hydrops (LMPH3, #616843), an autosomal recessive condition caused by biallelic loss-of-function mutations. We analyzed a 14-year-old boy affected by severe lymphatic dysplasia already present prenatally, with peripheral edema, hydrocele, and chylothoraces. By whole exome sequencing, we identified compound heterozygosity for , with one splicing and one deletion mutation, the latter causing the formation of a premature stop codon that leads to mRNA decay. The functional analysis of the erythrocytes of the patient highlighted altered hydration with the intracellular loss of the potassium content and structural abnormalities with anisopoikolocytosis and presence of both spherocytes and stomatocytes. This novel erythrocyte trait, sharing features with both hereditary spherocytosis and overhydrated hereditary stomatocytosis, complements the clinical features associated with loss-of-function mutations of in the context of the generalized lymphatic dysplasia of LMPH3 type.
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http://dx.doi.org/10.3389/fphys.2019.00258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428731PMC
March 2019

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

Mol Genet Genomic Med 2019 02 18;7(2):e00496. Epub 2018 Dec 18.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Background: Chromothripsis, which is the local massive shattering of one or more chromosomes and their reassembly in a disordered array with frequent loss of some fragments, has been mainly reported in association with abnormal phenotypes. We report three unrelated healthy persons, two of which parenting a child with some degree of intellectual disability, carrying a chromothripsis involving respectively one, two, and three chromosomes, which was detected only after whole-genome sequencing. Unexpectedly, in all three cases a fragment from one of the chromothripsed chromosomes resulted to be inserted within a nonchromothripsed one.

Methods: Conventional cytogenetic techniques, paired-end whole-genome sequencing, polymerase chain reaction, and Sanger sequencing were used to characterize complex rearrangements, copy-number variations, and breakpoint sequences in all three families.

Results: In two families, one parent was carrier of a balanced chromothripsis causing in the index case a deletion and a noncontiguous duplication at 3q in case 1, and a t(6;14) translocation associated with interstitial 14q deletion in case 2. In the third family, an unbalanced chromothripsis involving chromosomes 6, 7, and 15 was inherited to the proband by the mosaic parent. In all three parents, the chromothripsis was concurrent with an insertional translocation of a portion of one of the chromothriptic chromosomes within a further chromosome that was not involved in the chromothripsis event.

Conclusion: Our findings show that (a) both simple and complex unbalanced rearrangements may result by the recombination of a cryptic parental balanced chromothripsis and that (b) insertional translocations are the spy of more complex rearrangements and not simply a three-breakpoint event.
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http://dx.doi.org/10.1002/mgg3.496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393660PMC
February 2019

Small supernumerary marker chromosomes: A legacy of trisomy rescue?

Hum Mutat 2019 02 22;40(2):193-200. Epub 2018 Nov 22.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In other cases, the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic nondisjunction followed by postzygotic anaphase lagging of the supernumerary chromosome and its subsequent chromothripsis.
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http://dx.doi.org/10.1002/humu.23683DOI Listing
February 2019

De novo unbalanced translocations have a complex history/aetiology.

Hum Genet 2018 Oct 1;137(10):817-829. Epub 2018 Oct 1.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.
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http://dx.doi.org/10.1007/s00439-018-1941-9DOI Listing
October 2018

Early-onset movement disorder as diagnostic marker in genetic syndromes: Three cases of FOXG1-related syndrome.

Eur J Paediatr Neurol 2018 Mar 31;22(2):336-339. Epub 2018 Jan 31.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy. Electronic address:

FOXG1-related syndrome is a developmental encephalopathy with a high phenotypic variability. A movement disorder presenting at onset is one of the main features, along with microcephaly and severe psychomotor delay without regression. Specific brain MRI findings facilitate the diagnosis. We report three cases of FOXG1-related syndrome, focusing on clinical onset, brain MRI and evolution over time in order to identify common features despite the three different underlying genotypes (14q12 deletion including the FOXG1 gene, FOXG1 intragenic mutation, 14q12 deletion including PRKD1 and a region regulating FOXG1 expression). In conclusion, we stress the importance of considering genetic syndromes in the differential diagnosis of early-onset movement disorders.
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http://dx.doi.org/10.1016/j.ejpn.2018.01.007DOI Listing
March 2018

Chromothripsis and ring chromosome 22: a paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome).

J Med Genet 2018 04 29;55(4):269-277. Epub 2018 Jan 29.

Cytogenetics Laboratory, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.

Introduction: Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS.

Methods: Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism.

Results: WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial elements at one breakpoint junction disrupted the topological associating domain joining to the transcriptional coregulator . WES failed to detect BPP-associated variants.

Conclusions: Although we were unable to highlight the molecular basis of BPP, our data suggest that haploinsufficiency and misregulation, both associated with intellectual disability, contributed to the patient's NDD, while interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.
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http://dx.doi.org/10.1136/jmedgenet-2017-105125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869459PMC
April 2018

SOX2: Not always eye malformations. Severe genital but no major ocular anomalies in a female patient with the recurrent c.70del20 variant.

Eur J Med Genet 2018 Jun 31;61(6):335-340. Epub 2018 Jan 31.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

SOX2 variants have been identified in multiple patients with severe ocular anomalies and pituitary dysfunction, in addition to various systemic features. We investigated a 26-year-old female patient suffering from spastic paraparesis, hypoplasia of corpus callosum, hypogonadotropic hypogonadism (HH) and intellectual disability, who was monitored for over 20 years, allowing a detailed genotype-phenotype correlation along time. Whole exome sequencing on the patient and her relatives identified a de novo SOX2 c.70del20 variant, which has been frequently reported in individuals with SOX2-related anophthalmia. Importantly, our patient lacked major ocular phenotype but showed vaginal agenesis, a feature never reported before. Although the involvement of male urogenital tract (cryptorchidism, hypospadias, small penis), is a well known consequence of SOX2 variants, their effect on the female genitalia has never been properly addressed, even considering the paradoxical female excess of SOX2 cases in the literature. Our findings emphasize the importance of testing for SOX2 variants in individuals with HH and genital anomalies even though anophthalmia or microphthalmia are not observed. Moreover, our case strengthens the role of SOX2 as a master regulator of female gonadal differentiation, as widely demonstrated for other SOX genes related to 46, XX sex reversal, such as SOX3 and SOX9.
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http://dx.doi.org/10.1016/j.ejmg.2018.01.011DOI Listing
June 2018

A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations.

J Vis Exp 2017 12 1(130). Epub 2017 Dec 1.

INSERM INMED; Aix-Marseille University;

Birth defects that involve the cerebral cortex - also known as malformations of cortical development (MCD) - are important causes of intellectual disability and account for 20-40% of drug-resistant epilepsy in childhood. High-resolution brain imaging has facilitated in vivo identification of a large group of MCD phenotypes. Despite the advances in brain imaging, genomic analysis and generation of animal models, a straightforward workflow to systematically prioritize candidate genes and to test functional effects of putative mutations is missing. To overcome this problem, an experimental strategy enabling the identification of novel causative genes for MCD was developed and validated. This strategy is based on identifying candidate genomic regions or genes via array-CGH or whole-exome sequencing and characterizing the effects of their inactivation or of overexpression of specific mutations in developing rodent brains via in utero electroporation. This approach led to the identification of the C6orf70 gene, encoding for a putative vesicular protein, to the pathogenesis of periventricular nodular heterotopia, a MCD caused by defective neuronal migration.
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http://dx.doi.org/10.3791/53570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755514PMC
December 2017
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