The variability of SMCHD1 gene in FSHD patients: evidence of new mutations

Strafella, Claudia; Caputo, Valerio; Galota, Rosaria Maria; Campoli, Giulia; Bax, Cristina; Colantoni, Luca; Minozzi, Giulietta; Orsini, Chiara; Politano, Luisa; Tasca, Giorgio; Novelli, Giuseppe; Ricci, Enzo; Giardina, Emiliano; Cascella, Raffaella

doi:10.1093/hmg/ddz239

Cited by 13 publications

(19 citation statements)

References 41 publications

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“…We did not analyze the short sequence-length polymorphism in all participants, given that several studies have shown that different haplotypes can be carried by patients with FSHD. [5][6][7][8][9][10][11][12] The carriers of DRA with 7 to 8 RUs represent 20% of all carriers accrued by INRF (eFigure 1 in the Supplement). We enrolled only patients for whom clinical evaluation was performed with the CCEF by a properly trained physician who belonged to the Italian Clinical Network for FSHD (ICNF).…”

Section: Study Design and Participantsmentioning

confidence: 99%

“…It has to be noted that SMCHD1 variants as well as D4Z4 hypomethylation in the presence of the haplotype 4qA/PAS distal to the D4Z4 array have been found in patients with bosma arhinia and microphtalmia syndrome, a congenital disease with no associated muscle phenotype. [5][6][7][8][9][10][11][12] The classic FSHD phenotype is characterized by onset in the first or second decade of life with progressive facial, shoulder girdle, and pectoral muscle weakness and atrophy, often asymmetric. 13 Disease progression may lead to the involvement of abdominal muscles and distal lower extremity weakness, causing a steppage gait before impairment of pelvic girdle muscles.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Ruggiero¹,

Mele

Manganelli³

et al. 2020

JAMA Netw Open

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IMPORTANCE Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). OBJECTIVE To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). DESIGN, SETTING, AND PARTICIPANTS This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018. MAIN OUTCOMES AND MEASURES The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). RESULTS A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD.

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Section: Study Design and Participantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Ruggiero¹,

Mele

Manganelli³

et al. 2020

JAMA Netw Open

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“…Patients of both classes harbor a DUX4 allele with a polyadenylation signal. However, 95% of patients (FSHD1) have a deletion of between one and 10 large repeated units of D4Z4 and the rest (FSHD2) inherit a mutation in the SMCHD1 or DNMT3B genes [148][149][150]. SMCHD1 and DNMT3B also act as modifiers of disease severity in FSHD1 subjects [149,151].…”

Section: Facioscapulohumeral Muscular Dystrophymentioning

confidence: 99%

“…The main features of DNA methylation abnormalities in human monogenic diseases are listed in Table 1. [145][146][147][148][149][150][151][152][153][154] Loss of methylation (LOM); gain of methylation (GOM); uniparental disomy (UPD); full mutation (FM); premutation (PM); methylation-specific (MS); multiplex ligation probe-dependent amplification (MLPA); paternal (Pat); maternal (Mat); Beckwith-Wiedemann syndrome (BWS); Silver-Russell syndrome (SRS); Transient Neonatal Diabetes Mellitus (TNDM); pseudohypoparathyroidism 1b (PHP1b); Multi-Locus Imprinting Disturbances (MLID); Facioscapulohumeral Muscular Dystrophy (FSHD).…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation in the Diagnosis of Monogenic Diseases

Cerrato

Sparago

Ariani

et al. 2020

Genes

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DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

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“…Thus, this patient satisfied the diagnostic criteria of SOD 23 . Physical evaluation detected no clinical features indicative of FSHD2 26,27 , except for mild fatigability, mild mental retardation, and slight instability in walking on tiptoes and heels (Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency

Kinjo

Nagasaki

Muroya

et al. 2020

Sci Rep

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Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum. Hypogonadotropic hypogonadism (HH) is a multifactorial disorder that occurs either as an isolated hormonal abnormality (isolated HH, IHH) or in combination with other pituitary hormone deficiencies (combined pituitary hormone deficiency, CPHD) 1,2. HH is frequently accompanied by craniofacial and neurological abnormalities, such as microphthalmia, anosmia, and septum pellucidum/corpus callosum hypoplasia 2-6. The current understanding is that IHH and CPHD belong to a disease spectrum, which includes septo-optic dysplasia (SOD) and holoprosencephaly at the most severe end and IHH at the mildest end 1,7. This disease spectrum results from defective organogenesis from the cranial placodes 1,8. To date, more than 40 genes have been implicated in this disease spectrum 1,9. However, mutations in these genes account for only about 50% of IHH cases and less than 20% of CPHD cases, indicating that other causative genes remain to be identified 1,9. SMCHD1 encodes an epigenetic regulator that controls DNA methylation of multiple genomic loci 10-12. Previous studies have shown that SMCHD1 is involved in the regulation of several monoallelically expressed genes 11,13 , and is particularly enriched in the nuclear territory of the inactive X chromosome (Xi) 14, 15. Yet, the precise function of this protein remains to be clarified. Recently, heterozygous SMCHD1 mutations were identified in patients

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The variability of SMCHD1 gene in FSHD patients: evidence of new mutations

Cited by 13 publications

References 41 publications

Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

DNA Methylation in the Diagnosis of Monogenic Diseases

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency

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