ABSTRACT
The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.
Subject(s)
Intellectual Disability , Musculoskeletal Abnormalities , Pelger-Huet Anomaly , Cell Nucleus/genetics , Child , Chromatin , Humans , Intellectual Disability/genetics , Loss of Heterozygosity , Pelger-Huet Anomaly/geneticsABSTRACT
The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50â years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.
Subject(s)
Intellectual Disability , Microcephaly , Movement Disorders , Nervous System Malformations , Neurodevelopmental Disorders , Animals , Female , Humans , Male , ATP-Binding Cassette Transporters , Intellectual Disability/genetics , Movement Disorders/genetics , Nervous System Malformations/genetics , Neurodevelopmental Disorders/genetics , Tremor , Zebrafish , Infant , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle AgedABSTRACT
Spectrins are common components of cytoskeletons, binding to cytoskeletal elements and the plasma membrane, allowing proper localization of essential membrane proteins, signal transduction, and cellular scaffolding. Spectrins are assembled from α and ß subunits, encoded by SPTA1 and SPTAN1 (α) and SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5 (ß). Pathogenic variants in various spectrin genes are associated with erythroid cell disorders (SPTA1, SPTB) and neurologic disorders (SPTAN1, SPTBN2, and SPTBN4), but no phenotypes have been definitively associated with variants in SPTBN1 or SPTBN5. Through exome sequencing and case matching, we identified seven unrelated individuals with heterozygous SPTBN1 variants: two with de novo missense variants and five with predicted loss-of-function variants (found to be de novo in two, while one was inherited from a mother with a history of learning disabilities). Common features include global developmental delays, intellectual disability, and behavioral disturbances. Autistic features (4/6) and epilepsy (2/7) or abnormal electroencephalogram without overt seizures (1/7) were present in a subset. Identification of loss-of-function variants suggests a haploinsufficiency mechanism, but additional functional studies are required to fully elucidate disease pathogenesis. Our findings support the essential roles of SPTBN1 in human neurodevelopment and expand the knowledge of human spectrinopathy disorders.
Subject(s)
Autistic Disorder/genetics , Epilepsy/genetics , Intellectual Disability/genetics , Seizures/genetics , Spectrin/genetics , Adolescent , Adult , Autistic Disorder/diagnostic imaging , Autistic Disorder/pathology , Carrier Proteins/genetics , Child , Child, Preschool , Electroencephalography , Epilepsy/diagnostic imaging , Epilepsy/pathology , Female , Haploinsufficiency/genetics , Heterozygote , Humans , Intellectual Disability/diagnostic imaging , Intellectual Disability/pathology , Loss of Function Mutation/genetics , Male , Microfilament Proteins/genetics , Phenotype , Problem Behavior , Seizures/diagnostic imaging , Seizures/pathology , Exome Sequencing , Young AdultABSTRACT
INTRODUCTION: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder starting after 40 years old, spastic paraparesis and peripheral neuropathy. It is mainly resultant from the GBE1 homozygous p.Tyr329Ser (c.986A>C) mutation, especially in Ashkenazi-Jewish patients, although some cases of compound heterozygous have been reported. A genotype-phenotype correlation is not established, but atypical phenotypes have been described mainly in non-p.Tyr329Ser pathogenic variants. CASE REPORT: We describe an atypical case in a 62-year-old Portuguese woman, presenting the typical clinical triad of APBD plus prominent autonomic dysfunction, suggested by orthostatic hypotension and thermoregulatory dysfunction; she has compound heterozygous GBE1 mutations, namely, p.Asn541Asp (c.1621A>G) and p.Arg515Gly (c.1543C>G), the last one not yet reported in literature and whose pathogenicity was suggested by bioinformatics analysis and confirmed by sural nerve biopsy that showed intra-axonal polyglucosan bodies. DISCUSSION: Besides the report of a novel GBE1 mutation, this case also expands the phenotypic spectrum of this disorder, reinforcing autonomic dysfunction as a possible and prominent manifestation of APBD, mimicking autosomal dominant leukodystrophy with autonomic disease in some way. Therefore, we questioned a possible relationship between this genotype and the phenotype marked by dysautonomia. Additionally, we review previously reported cases of APBD in non-homozygous p.Tyr329Ser patients with atypical phenotypes.
Subject(s)
Glycogen Debranching Enzyme System , Glycogen Storage Disease , Nervous System Diseases , Adult , Female , Glycogen Debranching Enzyme System/genetics , Homozygote , Humans , Middle Aged , MutationABSTRACT
Congenital adrenal hyperplasia (CAH) is a group of rare orphan disorders caused by mutations in seven different enzymes that impair cortisol biosynthesis. The 17α-hydroxylase deficiency (17OHD) is one of the less common forms of CAH, corresponding to approximately 1% of the cases, with an estimated annual incidence of 1 in 50,000 newborns. Cases description - two phenotypically female Ecuadorian sisters, both with primary amenorrhea, absence of secondary sexual characteristics, and osteoporosis. High blood pressure was present in the older sister. Hypergonadotropic hypogonadism profile was observed: decreased cortisol and dehydroepiandrosterone sulfate (DHEAS), increased adrenocorticotropic hormone (ACTH) and normal levels of 17-hydroxyprogesterone, extremely high deoxycorticosterone (DOC) levels, and a tomography showed bilateral adrenal hyperplasia in both sisters. Consanguinity was evident in their ancestors. Furthermore, in the exon 7, the variant c.1216T > C, p.Trp406Arg was detected in homozygosis in the CYP17A1 gene of both sisters. We report a homozygous missense mutation in the CYP17A1 gene causing 17OHD in two sisters from Loja, Ecuador. According to the authors, this is the first time such deficiency and mutation are described in two members of the same family in Ecuador.
Subject(s)
Adrenal Hyperplasia, Congenital/genetics , Siblings , Steroid 17-alpha-Hydroxylase/genetics , 17-alpha-Hydroxyprogesterone/metabolism , Adrenal Hyperplasia, Congenital/complications , Adrenal Hyperplasia, Congenital/metabolism , Adrenocorticotropic Hormone/metabolism , Amenorrhea/etiology , Consanguinity , Dehydroepiandrosterone Sulfate/metabolism , Desoxycorticosterone/metabolism , Diagnostic Errors , Ecuador , Female , Homozygote , Humans , Hydrocortisone/metabolism , Hypertension/etiology , Hypogonadism/etiology , Hypogonadism/metabolism , Hypokalemia/etiology , Mosaicism , Osteoporosis/etiology , Turner Syndrome/diagnosis , Young AdultABSTRACT
PURPOSE: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.
Subject(s)
Carboxy-Lyases/genetics , Carboxy-Lyases/metabolism , Adolescent , Adult , Brazil , Exome/genetics , Female , Genotype , HEK293 Cells , Hearing Loss, Sensorineural/genetics , Humans , Intellectual Disability/genetics , Male , Microcephaly/genetics , Musculoskeletal Abnormalities/genetics , Osteochondrodysplasias/genetics , Pedigree , Phenotype , Portugal , Retinal Degeneration/genetics , Syndrome , Young AdultABSTRACT
Adams-Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb malformations of variable severity. When neurological findings are present, patients are reported as AOS variants. We describe a child with compound heterozygosity of the DOCK6 gene, aplasia cutis, terminal transverse limb defects, cardiovascular impairment, intellectual disability, and brain malformations with intracranial calcifications. He suffers from a severe refractory epileptic encephalopathy characterized by polymorphic seizures with prolonged periods of electroencephalogram (EEG), continuous epileptiform activity related to clinical inactivity, and closure of eyes with an "ON-OFF" behavior.
Subject(s)
Ectodermal Dysplasia/genetics , Epilepsy/genetics , Guanine Nucleotide Exchange Factors/genetics , Limb Deformities, Congenital/genetics , Mutation , Scalp Dermatoses/congenital , Brain/physiopathology , Ectodermal Dysplasia/physiopathology , Epilepsy/physiopathology , Humans , Infant , Limb Deformities, Congenital/physiopathology , Male , Phenotype , Scalp Dermatoses/genetics , Scalp Dermatoses/physiopathologyABSTRACT
INTRODUCTION: CMT4B2 is a rare subtype of CMT caused by pathogenic mutations in the myotubularin-related protein-13/set binding factor 2 (MTMR13/SBF2) gene. Nerve conduction velocities are markedly reduced and focally folded myelin sheaths are present on nerve biopsies. We presented two patients from two related Portuguese families with peripheral neuropathy caused by a novel mutation in the MTMR13/SBF2 gene. CASE REPORT: Family 1: Patient 1: A 30-year-old woman, with disease onset in early childhood presented pes cavus and hammertoes and walked with a steppage gait. Muscle weakness was present distally, myotactic reflexes were abolished and sensory examination revealed a stocking and glove pattern of hypoesthesia to all sensory modalities. Family 2: Patient 2: A 43-year-old man, second degree cousin of patient 1, born of a consanguineous marriage. At the age of 9 months, he was diagnosed with congenital glaucoma on the left eye, with progressive visual loss up to total blindness. He presented bilateral claw hand deformity, pes cavus and hammertoes and walked with a steppage gait. Myotactic reflexes were abolished and muscle weakness was severe distally in the upper and lower limbs. Sensory examination revealed a stocking and glove pattern of hypoesthesia to all modalities. In both patients electrodiagnostic studies evidenced an uniform and generalized sensorimotor demyelinating polyneuropathy and the molecular study found a frameshift/truncating homozygous novel mutation c.5073_5074del (p.Ser1692Tyrfs*42) in the MTMR13/SBF2 gene. CONCLUSIONS: We report a novel mutation in the MTMR13/SBF2 gene associated with a classical CMT phenotype. Congenital glaucoma associated with a frameshift/truncating mutation in CMT4B2 is reported for the first time.
Subject(s)
Charcot-Marie-Tooth Disease , Glaucoma , Peripheral Nervous System Diseases/etiology , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Adult , Charcot-Marie-Tooth Disease/complications , Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Consanguinity , Female , Glaucoma/congenital , Glaucoma/etiology , Humans , Male , Mutation , Neurophysiological Monitoring/methods , PortugalSubject(s)
Blindness/congenital , Drug Resistant Epilepsy/etiology , Genetic Diseases, X-Linked/complications , Nervous System Diseases/complications , Retinal Degeneration/complications , Spasms, Infantile/complications , Adolescent , Blindness/complications , Blindness/diagnosis , Blindness/physiopathology , Blindness/therapy , Drug Resistant Epilepsy/diagnosis , Drug Resistant Epilepsy/physiopathology , Drug Resistant Epilepsy/therapy , Eye Proteins/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/physiopathology , Genetic Diseases, X-Linked/therapy , Humans , Male , Nerve Tissue Proteins/genetics , Nervous System Diseases/diagnosis , Nervous System Diseases/physiopathology , Nervous System Diseases/therapy , Retinal Degeneration/diagnosis , Retinal Degeneration/physiopathology , Retinal Degeneration/therapy , Sequence Deletion , Siblings , Spasms, Infantile/diagnosis , Spasms, Infantile/physiopathology , Spasms, Infantile/therapyABSTRACT
Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients' clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype-phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0-64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype-phenotype relationships for "frequent" NPC1 variants.
Subject(s)
Phenotype , Adult , Humans , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , Middle AgedABSTRACT
PURPOSE: Hereditary spastic paraplegias compose a group of neurodegenerative disorders with a large clinical and genetic heterogeneity. Among the autosomal recessive forms, spastic paraplegia type 11 is the most common. METHODS: To better understand the spastic paraplegia type 11 mutation spectrum, we studied a group of 54 patients with hereditary spastic paraplegia. Mutation screening was performed by PCR amplification of SPG11 coding regions and intron boundaries, followed by sequencing. For the detection of large gene rearrangements, we performed multiplex ligation-dependent probe amplification. RESULTS: We report 13 families with spastic paraplegia type 11 carrying either novel or previously identified mutations. We describe a complex entire SPG11 rearrangement and show that large gene rearrangements are frequent among patients with spastic paraplegia type 11. Moreover, we mapped the deletion breakpoints of three different large SPG11 deletions and provide evidence for Alu microhomology-mediated exon deletion. CONCLUSION: Our analysis shows that the high number of repeated elements in SPG11 together with the presence of recombination hotspots and the high intrinsic instability of the 15q locus all contribute toward making this genomic region more prone to large gene rearrangements. These findings enlarge the amount of data relating repeated elements with neurodegenerative disorders and highlight their importance in human disease and genome evolution.
Subject(s)
Alu Elements , Mutation , Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Alleles , Amino Acid Sequence , Base Sequence , Child , Child, Preschool , Chromosome Breakpoints , Exons , Female , Gene Order , Genotype , Humans , Infant , Male , Middle Aged , Molecular Sequence Data , Pedigree , Sequence Deletion , Young AdultABSTRACT
To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.
Subject(s)
DNA Copy Number Variations , Metabolic Diseases , Exome , High-Throughput Nucleotide Sequencing , Humans , Metabolic Diseases/diagnosis , Metabolic Diseases/genetics , Pakistan , Exome SequencingABSTRACT
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expansions of 55-200 CGG repeats in the 5'UTR of the FMR1 gene. These FMR1 premutation expansions have relatively high frequency in the general population. To estimate the frequency of FMR1 premutations among Portuguese males with non-familial, late-onset movement disorders of unknown etiology, we assessed CGG repeat size in males with disease onset after the age of 50 and negative or unknown family history for late-onset movement disorders, who were sent for SCA, HD, or PD genetic testing at a reference laboratory. The selected patients had a primary clinical diagnosis based on one of the following cardinal features of FXTAS: ataxia, tremor, or cognitive decline. A total of 86 subjects were genotyped for the CGG repeat in the FMR1 gene. We detected one patient with an expansion in the premutation range. The frequency of FMR1 premutations was 1.9% (1/54) in our group of patients with ataxia as the primary clinical feature, and 1.2% (1/86) in the larger movement disorders group. In the family of the FXTAS case, premutation-transmitting females presented a history of psychiatric symptoms, suggesting that, given the wide phenotypical expression of the premutation in females, neuropsychiatric surveillance is necessary. In conclusion, genetic testing for FXTAS should be made available to patients with adult-onset movement disorders to enable adequate genetic counseling to family members.
Subject(s)
Ataxia/genetics , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Mutation/genetics , Tremor/genetics , Aged , Ataxia/complications , Fragile X Syndrome/complications , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Middle Aged , Pedigree , Phenotype , Portugal , Tremor/complications , Trinucleotide Repeat Expansion/geneticsABSTRACT
CMT disease caused by NEFL gene mutations is rare. The mode of inheritance can be dominant or recessive and nerve conduction velocities can be normal, reduced (demyelinating) or presenting intermediate values. Two Portuguese adult related members in two successive generations were affected by peripheral neuropathy, one with a chronic ataxic peripheral neuropathy and the other with a classical Charcot-Marie-Tooth phenotype. An axonal sensorimotor peripheral neuropathy was described at neurophysiology. A missense heterozygous mutation, c.794A > G (p.Tyr265Cys), in the NEFL gene was found in both patients. This is the first Portuguese family reported with NEFL-related CMT type 2.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Neurofilament Proteins/genetics , Peripheral Nervous System Diseases/genetics , Aged , Female , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , Phenotype , PortugalABSTRACT
BACKGROUND: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID). RESULTS: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed. CONCLUSIONS: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.
Subject(s)
Intellectual Disability/genetics , Chromosome Aberrations , Comparative Genomic Hybridization , DNA Copy Number Variations/genetics , Female , Genetic Association Studies , Genomics , Histone-Lysine N-Methyltransferase/genetics , Humans , Male , Pedigree , PhenotypeABSTRACT
Mutations in early B cell factor 3 (EBF3) were recently described in patients with a neurodevelopmental disorder (NDD) that includes developmental delay/intellectual disability, ataxia, hypotonia, speech impairment, strabismus, genitourinary abnormalities, and mild facial dysmorphisms. Several large 10q terminal and interstitial deletions affecting many genes and including EBF3 have been described in the literature. However, small deletions (<1 MB) affecting almost exclusively EBF3 are not commonly reported. We performed array comparative genomic hybridization (aCGH) (Agilent 180K) and quantitative PCR analysis in a female patient with intellectual disability. A clinical comparison between our patient and overlapping cases reported in the literature was also made. The patient carries a de novo 600 Kb deletion at 10q26.3 affecting the MGMT, EBF3, and GLRX genes. The patient has severe intellectual disability, language impairment, conductive hearing loss, hypotonia, vision alterations, triangular face, short stature, and behavior problems. This presentation overlaps that reported for patients carrying EBF3 heterozygous point mutations, as well as literature reports of patients carrying large 10qter deletions. Our results and the literature review suggest that EBF3 haploinsufficiency is a key contributor to the common aspects of the phenotype presented by patients bearing point mutations and indels in this gene, given that deletions affecting the entire gene (alone or in addition to other genes) are causative of a similar syndrome, including intellectual disability (ID) with associated neurological symptoms and particular facial dysmorphisms.
ABSTRACT
Mutations of the encoding genes of collagen VI (COL6A1, COL6A2 and COL6A3), are responsible for two classical phenotypes (with a wide range of severity), the Ullrich congenital muscular dystrophy (UCMD) and the Bethlem myopathy (BM). We present a male patient of 49 years old, with symptoms of muscle weakness beginning in childhood and of very slowly progression. At the age of 42, the neurological examination revealed proximal lower limb muscle weakness and contractures of fingers flexors muscles, positive Gowers manoeuvre and a waddling gait. Serum creatine kinase (CK) values were slightly elevated, electromyographic study revealed myopathic changes and muscle MRI of the lower limbs showed a specific pattern of muscle involvement, with peripheral fat infiltration in vastus lateralis and intermedius and anterocentral infiltration in rectus femoris. Respiratory and cardiac functions were unremarkable. Whole exome sequencing identified the homozygous mutation c.1970-9G>A in COL6A2 gene.
Subject(s)
Collagen Type VI/genetics , Contracture/etiology , Fingers , Muscle Weakness/etiology , Muscular Dystrophies/congenital , Contracture/complications , Contracture/diagnosis , Contracture/genetics , Gait , Homozygote , Humans , Male , Middle Aged , Muscular Dystrophies/complications , Muscular Dystrophies/diagnosis , Muscular Dystrophies/genetics , Mutation , PortugalABSTRACT
BACKGROUND: Some patients exhibit features of both autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Similarly, patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) may share histological features with PSC. CASE REPORT: We report the case of a 22-year-old man who, since he was 5 years of age, has presented with pruritus, an approximately ninefold elevation of aminotransferases, and γ-glutamyl transferase levels ~10 times the upper limit. Initially he was diagnosed with an overlap syndrome of small duct PSC plus AIH. However, fluctuations in liver enzymes were observed over the following years. Analysis of the ABCB4 gene indicated the diagnosis of PFIC3, revealing a mutation not previously reported. CONCLUSION: With this case report we aim to describe a new mutation, raise awareness of this rare pathology and highlight the importance of genetic testing of the ABCB4 gene in patients with autoimmune liver disease (mainly small duct PSC) with incomplete response to immunosuppressive treatment. LEARNING POINTS: Autoimmune liver diseases have a wide spectrum of manifestations.Cholangiopathies such as ABCB4 deficiency have histological features quite similar to those seen in small duct primary sclerosing cholangitis.The new mutation of the ABCB4 gene described in this article is compatible with the diagnosis of progressive familial intrahepatic cholestasis type 3, which is probably less rare than usually thought.
ABSTRACT
BACKGROUND: There are three types of progressive familial intrahepatic cholestasis (PFIC). Type 3 is characterized by elevated gamma-glutamyl transferase (γ-GT) and it can be diagnosed in adolescence/adulthood. The genetic defect of PFIC 3 appears to explain the pathogenesis of intrahepatic cholestasis of pregnancy (ICP). AIMS: Draw attention to this rare disease, especially in adulthood, and clarify the association between ICP and PFIC 3. RESULTS: We describe a series of cases from a Portuguese northern family with two brothers presenting chronic cholestasis since adolescence. Brother 1: since 15-years-old with pruritus and elevated γ-GT â¼6x. Brother 2: pre-term, due to severe maternal pruritus and jaundice, since 13-years-old with pruritus, jaundice and â¼8x γ-GT elevation. Common causes of cholestasis were excluded and liver histologies were nonspecific. Research for mutation on ABCB4 gene showed mutations in both alleles. CONCLUSION: Disease and mechanisms that determine cholestasis are complex and their understanding may provide new therapeutics.