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2.
J Hum Genet ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785861

RESUMO

Monoallelic mutations on TMEM63A have been recently reported as cause of a previously unrecognized disorder named "infantile-onset transient hypomyelination". Clinical and neuroradiological presentation is described as highly similar to Pelizaeus-Merzbacher Disease but evolution over time was surprisingly benign with a progressive spontaneous improving course. We report on a new TMEM63A-mutated girl. The clinical picture was similar to the one already described except for the presence of recurrent episodes of unilateral eyelid twitching, and for the evidence of spinal cord involvement on MRI. These are interesting findings helping in distinguishing this condition from classic PMD since early disease stages. However, additional observations are needed to confirm if these are common features of this condition.

3.
Am J Hum Genet ; 108(3): 502-516, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33596411

RESUMO

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos X/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genética , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Adulto Jovem
4.
Clin Dysmorphol ; 30(1): 39-43, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33086257

RESUMO

Pathogenic variants of HIST1H1Egene have recently been associated with a condition known as Rahman syndrome, characterized by overgrowth, intellectual disability and nonspecific dysmorphic features (high hairline, full cheeks, wide nasal bridge). Wide clinical variability is reported, especially regarding the level of neurodevelopment delay and intellectual disability. We report a 10-year-old girl with macrocephaly and global developmental delay, in whom a novel heterozygous variant in the HIST1H1Egene [c.392_395dup (p.Gly133fs)] was discovered, but involving the same C-terminal domain-protein domain reported previously. Comparing the clinical data of our patient with those previously described, a 'core phenotype' with macrocephaly, psychomotor delay/intellectual disability and mild facial dysmorphisms seems evident.

5.
Genet Med ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33173220

RESUMO

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

6.
J Am Coll Cardiol ; 76(19): 2238-2247, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33153584

RESUMO

BACKGROUND: The mitral valve is often structurally abnormal in hypertrophic cardiomyopathy (HCM). However, the mechanisms responsible for these abnormalities remain controversial. In 2016 we identified, at myectomy, muscular mitral-aortic discontinuity in 5 young patients with obstructive HCM. OBJECTIVES: This study sought to confirm our preliminary findings and assess the prevalence of muscular mitral-aortic discontinuity in obstructive HCM. METHODS: At our center, from January 2017 to April 2018, the area between the anterior mitral leaflet and aortic valve was inspected at myectomy in 106 consecutive patients with HCM. RESULTS: Muscular mitral-aortic discontinuity was identified in 28 (26%) patients and was significantly more common in younger than older patients (age 39 ± 13 years vs. 58 ± 11 years; p < 0.001). Muscular discontinuity was present in each of 6 patients aged <30 years but only 1 (2.7%) of 37 aged ≥60 years. Pathogenic sarcomere mutations were identified in 22 (79%) of 28 patients with and 24 (31%) of 78 without discontinuity (p < 0.001) and were associated with discontinuity independently of age (p = 0.021). Discontinuity mean length was 7.3 mm and was inversely related to age (p = 0.022). At echocardiography, the anterior mitral leaflet was longer in patients with than those without discontinuity (34 ± 4 mm vs. 29 ± 5 mm; p < 0.001). CONCLUSIONS: We report, for the first time, muscular mitral-aortic discontinuity in HCM. At myectomy, a long muscular discontinuity displaced the anterior mitral leaflet toward the apex in most young patients, was significantly associated with sarcomere mutations independent of age, and was extremely uncommon in older patients. These findings suggest that a long muscular mitral-aortic discontinuity could predispose to the development of outflow obstruction in young patients with sarcomere mutations.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33151750

RESUMO

Background - The X-linked Danon disease (DD) manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease (DD) in cardiomyopathy centers throughout Europe. Methods - Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results - The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 yr. in males and 2-65 in females. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in males but not in females. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of males (who had LVEF 34±11%) and 59% of females (LVEF 28±13%). The risk of arrhythmia and heart failure (HF) were comparable among genders. The age of first HF hospitalization was lower in males (18 ± 6 vs. 28 ±17 yr., p<0.003). HF was the leading cause of death (10/17, 59%), and LV systolic dysfunction predicted an adverse outcome. Eight males and 8 females (28%) underwent heart transplantation or received a left ventricular assist device (LVAD). Our cohort suggests better prognosis of female compared to male heart transplant recipients. Conclusions - DD presents earlier in males than females and runs a malignant course in both genders, due to cardiac complications. Cardiomyopathy features: heart failure and arrhythmia, are similar among the genders. Clinical diagnosis and management is extremely challenging in females due to phenotypic diversity and absence of extracardiac manifestations.

8.
Am J Med Genet A ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058492

RESUMO

Congenital glycosylation disorders (CDG) are inherited metabolic diseases due to defective glycoprotein and glycolipid glycan assembly and attachment. MOGS-CDG is a rare disorder with seven patients from five families reported worldwide. We report on a 19-year-old girl with MOGS-CDG. At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures. In the following months, her motility was strongly limited by dystonia, with forced posture of the head and of both hands. She showed a peculiar hyperkinetic movement disorder with a rhythmic and repetitive pattern repeatedly documented on EEG-polygraphy recordings. Brain MRI showed progressive cortical and subcortical atrophy. Epileptic spasms appeared in first months and ceased by the age of 7 years, while tonic seizures were still present at last assessment (19 years). We report the oldest-known MOGS-CDG patient and broaden the neurological phenotype of this CDG.

9.
Blood ; 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32905580

RESUMO

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated three novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound heterozygous variants in the gene for Folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and PI3K/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy number variants [CNV] in two patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

10.
Brain ; 143(8): 2437-2453, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32761064

RESUMO

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

11.
Eur J Paediatr Neurol ; 28: 151-158, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32800686

RESUMO

INTRODUCTION: ECHS1 encodes for short-chain enoyl-CoA hydratase, a key component in b-oxidation. This enzyme is also involved in the isoleucine and valine catabolic pathways. The literature contains reports of scattered cases of ECHS1 mutation, which show a wide clinical spectrum of presentation. Despite that the clinical spectrum of the disease has not been defined so far due to the absence of previous systematic reviews and descriptions of large series of patients. METHODS: We performed a systematic literature review of so far reported ECHS1 mutated patients and we reported two additional cases. We pointed out clinical and neuroradiological features of all patients. RESULTS: 45 patients were included in the analysis. Based on clinical and neuroradiological feature we were able to distinguish four main phenotypes of ECHS1deficiency: a severe neonatal presentation with a rapid and fatal course and significant white matter abnormalities; a severe infantile variant with slower neurological deterioration, developmental delay, pyramidal and extrapyramidal signs, optic atrophy, feeding difficulties, and degeneration of the deep gray nuclei; a slowly progressive infantile form, qualitatively similar to the previous phenotype, but less severe with mainly basal ganglia involvement; and a final phenotype, present in only few cases, characterized by paroxysmal exercise-induced dystonic attacks, normal neurological examination between these episodes, and isolated pallidal degeneration on MRI. INTERPRETATION: ECHS1 mutations cause metabolic encephalopathy with a wide range of clinical presentations that can be grouped into four main phenotypes, each with a distinct profile in terms of severity on clinical presentation, disease course and MRI involvement.

12.
Genet Med ; 22(7): 1215-1226, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32376980

RESUMO

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

13.
Mol Genet Genomic Med ; 8(7): e1278, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32412696

RESUMO

BACKGROUND: The Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder (OMIM615722) mostly characterized by optic atrophy and/or hypoplasia, mild intellectual disability, hypotonia, seizures/infantile epilepsy. This disorder is caused by loss-of-function alterations of NR2F1 (i.e., either whole gene deletions or single nucleotide variants) and, to date, 40 patients have been identified with deletions or mutations in this gene. Here we describe two monozygotic twins harboring a de novo missense variant in the DNA-binding domain of NR2F1 (c.313G>A, p.Gly105Ser), with well-characterized features associated to BBSOAS. METHODS: Patients' DNA was analyzed by exome sequencing identifying the missense variant c.313G>A in NR2F1 (NM_005654.4). Furthermore, molecular modeling was performed to evaluate putative differences in DNA binding between wild-type and mutated NR2F1. RESULTS: The missense variant is predicted to be likely pathogenetic following the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines. Indeed, dynamic simulation experiments highlighted that the Gly105Ser substitution let the formation of a hydrogen bond between the S105 side chain and R142 and a base (G5) of the DNA sequence, allowing us to hypothesize that the G105 residue might be evolutionary conserved due to the absence of a side chain, besides glycine conformational features. Therefore, the G105S variation seems to cause a stiffening and a possible deformation in the protein-DNA complex due to the interaction of residues R142-S105 and G5 on the DNA, compared to the wild-type. CONCLUSION: In summary, we described two monozygotic twins harboring a novel Gly105Ser mutation in NR2F1 DNA binding domain, displaying the classical phenotype of BBSOAS-affected patients. Our computational data suggest a dominant negative effect of this newly characterized missense variant. To date, this is the first genetic report analyzing in silico structural consequences of NR2F1 Gly105Ser substitution.

14.
J Pediatr Genet ; 9(2): 132-136, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32341819

RESUMO

Sleep-disordered breathing (SDB) is common in children, especially in those with congenital or genetic diseases. The factors involved include obstructive sleep apnea, disrupted rapid eye movement sleep, and central hypoventilation. Diagnosing and treating SDB in these children have a positive impact on the quality of life of them and their families, reducing the risk of both further impairment of cognitive abilities and cardiopulmonary complications. We report a familial case of SDB with central hypoventilation, in which identification of the disorder in the younger sister led to the unfortunately late diagnosis and treatment of the same condition in the older sister.

15.
Clin Genet ; 98(1): 91-98, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32335897

RESUMO

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.

16.
Am J Hum Genet ; 106(5): 596-610, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32243864

RESUMO

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação , Complexo Repressor Polycomb 2/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mosaicismo , Mutação de Sentido Incorreto/genética , Reprodutibilidade dos Testes , Adulto Jovem
17.
Am J Hum Genet ; 106(4): 570-583, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197074

RESUMO

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.


Assuntos
Deficiências do Desenvolvimento/genética , Variação Genética/genética , Leucoencefalopatias/genética , Malformações do Sistema Nervoso/genética , eIF-2 Quinase/genética , Adolescente , Ataxia/genética , Criança , Pré-Escolar , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Lactente , Masculino , Substância Branca/patologia
19.
Am J Med Genet A ; 182(6): 1477-1482, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32198969

RESUMO

Inherited glycosylphosphatidylinositol (GPI) deficiencies are a group of clinically and genetically heterogeneous conditions belonging to the congenital disorders of glycosylation. PIGW is involved in GPI biosynthesis and modification, and biallelic pathogenic variants in this gene cause autosomal recessive GPI biosynthesis defect 11. Only five patients and two fetuses have been reported in the literature thus far. Here we describe a new patient with a novel homozygous missense variant in PIGW, who presented with hypotonia, severe intellectual disability, early-onset epileptic seizures, brain abnormalities, nystagmus, hand stereotypies, recurrent respiratory infections, distinctive facial features, and hyperphosphatasia. Our report expands the phenotype of GPI biosynthesis defect 11 to include stereotypies and recurrent respiratory infections. A detailed and long-term analysis of the electroclinical characteristics and review of the literature suggest that early-onset epileptic seizures are a key manifestation of GPI biosynthesis defect 11. West syndrome and focal-onset epileptic seizures are the most common seizure types, and the fronto-temporal regions may be the most frequently involved areas in these patients.

20.
Mol Genet Genomic Med ; 8(3): e1064, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31943948

RESUMO

BACKGROUND: In the last few years trio-whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases. Moreover WES allows the detection of variants in multiple genes causing different genetic conditions in a single patient, in about 5% of cases. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition. METHODS: Trio-WES was performed on a 4-month-old baby with a complex clinical presentation characterized by skeletal anomalies, congenital heart malformation, congenital hypothyroidism, generalized venous and arterial hypoplasia, and recurrent infections. RESULTS: WES detected two different homozygous variants, one in CEP57, the gene responsible for mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short-rib thoracic dysplasia. CONCLUSION: The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants. The report then highlights the role of WES in providing complete and fast diagnosis in patients with complex presentations of rare genetic syndromes, with important implications in the assessment of recurrence risk.

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