Novel findings of left ventricular non‐compaction cardiomyopathy, microform cleft lip and poor vision in patient with <i>SMC1A</i>‐associated Cornelia de Lange syndrome

Wenger, Tara L.; Chow, Penny; Randle, Stephanie C.; Rosén, Anna; Birgfeld, Craig; Wrede, Joanna E; Javid, Patrick J.; King, Darcy; Manh, Vivian; Hing, Anne V.; Albers, E.

doi:10.1002/ajmg.a.38030

Cited by 14 publications

(15 citation statements)

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“…SMC1A mutations can cause early onset epilepsy only in females with cluster seizures. At present, a spectrum of SMC1A gene have been related with Cornelia de Lange syndrome (CdLS), SMC1A-related encephalopathy only with female patients, colorectal carcinomas, bladder cancer and leukemia [15][16][17][18][19][20][21][22]. Consistent with previous clinical reports, our 3 patients have moderate to severe neurological impairment and epilepsy.…”

Section: Discussionsupporting

confidence: 89%

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Liu

Luo

et al. 2021

Preprint

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Background To explore the clinical phenotype and long-term outcome in children with genetic causes of early-onset epileptic encephalopathies. Methods The clinical data of 118 children between 2010 and 2020 was obtained and analyzed. The whole exome sequencing and copy number variation studies in family were used to find pathogenic mutations. The confirmed mutations were verified by Sanger sequencing. Results Among 118 patients, 39 patients were diagnosed with DS, 18 were WS, 3 were OS, 3 were EME, 2 were MMFSI, 1 was GLUT1 deficiency syndrome, 1 was Pyridoxine dependent epilepsy and 51 were non-symptomatic EOEEs. The initial EEG showed frequent multiple and multifocal sharp waves, spike waves, sharp slow waves or spike slow waves. In the later period, some transformed into infrequent discharging or normal EEG. 112 patients (112/118, 94.9%) showed normal brain MRI, and the remaining 6 had widened extracerebral space. In the later stage, 115 patients were re-examined with brain MRI 1 to 3 times, the widened gap became normal, only 2 had mild brain atrophy. After treatment, 42 patients (42/118, 35.6%) had seizure control. In EOEE-BS, 6 patients were found KCNQ2 mutations and the remaining mutations were SCN2A (n=2), STXBP1 (n=1). After treatment, only 2 patients had seizure control, 6 had uncontrolled seizures and 1 died. 7 patients with dyskinesia were found. 1 patient starting with a febrile convulsion was caused by HNRNPU mutation. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. The second common mutations were KCNQ2 mutations in 9 patients. The third one was CDKL5 mutations in 8 patients. Genes associated with ionic channels represented the largest proportion (66/118, 55.9%), sodium channel potassium channel and calcium channel respectively. In WS, we detected SCN3A, SCN2A, SCN8A, CACNA1H, DEPDC5, MECP2, DYNC1H1, CDKL5, ALG11, CCDC88C, GABAA1, IL1RAPL1, RNASEH2B, SLC19A3, STXBP1, QARS, COL4A2 mutations. In addition to common gene mutations, we reported rare possible pathogenic genes: CCDC88C, IL1RAPL1, RNASEH2B and COL4A2 in WS. In non-syndromic genetic causes of EOEEs, we detected rare possible pathogenic genes: SETBP1, DPYD, CSNK2B and H3F3A. As for genetic modes, denovo heterozygous mutations account for the largest proportion (104/118, 88.1%). 3 patients with SMC1A mutations response to KD add-on therapy. VPA added treatment showed good effects on KCNB1 and PACS2 encephalopathy. LEV showed good effects on STXBP1, and OXC showed good effects on SCN8A encephalopathy. Conclusion The clinical manifestations of EOEE are variable, including dyskinesia. EOEE-BS usually response poorly to AEDS therapy. Although some patients achieve seizure-free, there is no remarkable improvement in their development. EOEEs starting with a febrile convulsion may be a special phenotype of HNRNPU related neurodevelopmental syndrome, similar to DS. We report rare possible pathogenic genes: CCDC88C, IL1RAPL1, RNASEH2B, COL4A2 in WS and detect rare possible pathogenic genes: SETBP1, DPYD, CSNK2B and H3F3A in non-syndromic genetic causes of EOEEs. Although genetic causes of EOEEs response poorly to AEDS treatment, we find that some gene mutation related EOEEs receive good effects on specific AEDS.

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Section: Discussionsupporting

confidence: 89%

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Liu

Luo

et al. 2021

Preprint

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“…CHD with SMC1A -associated CdLS has been previously reported in 13 cases, including ours, yet this is the first report including a TGA diagnosis (Supplementary Table 1) 2–4,6,12–18 . In patients with CHD, the rate of substitution or mutation at an arginine position is 42% (5/12), and in patients without CHD, the rate is 50% (11/22).…”

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confidence: 69%

“…A review of the literature revealed 60 cases of SMC1A -associated CdLS with a male-to-female ratio of 1:2 3 . A total of nine cases of CdLS with congenital cardiac defects (CHD) have been reviewed 4 , although the incidence of CHD in patients with CdLS is ~30% 5 . SMC1A -related CdLS arises from a dominant negative effect in females 2 .…”

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confidence: 99%

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A novel nonsense SMC1A mutation in a patient with intractable epilepsy and cardiac malformation

et al. 2019

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Cornelia de Lange syndrome (CdLS) is a cohesinopathy caused by genetic variations. We present a female with SMC1A -associated CdLS with a novel SMC1A truncation mutation (p. Arg499Ter), transposition of the great arteries, and periodic intractable seizures from 40 months of age. A review of the literature revealed that a seizure-free period after birth of at least 15 months is required for these patients to be able to walk, irrespective of the epileptic course.

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“…Intriguingly, cases have been increasingly reported of females with heterozygous de novo SMC1A pathogenic variants, mostly loss-of-function mutations (LOFs). These variants are associated with a more severe clinical phenotype of developmental and epileptic encephalopathy (DEE), a devastating form of early onset intractable epilepsy beginning in infancy and associated with global developmental delay, cognitive dysfunction, and ongoing epileptiform activity [ 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Most reported cases did not show significant brain MRI abnormalities, but cases with holoprosencephaly have been reported [ 15 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy

Bozarth

Lopez

et al. 2023

Genes

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The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in SMC1A are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features; however, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Unlike the male-to-female ratio of 1:2 in those with CdLS associated with dominant-negative SMC1A variants, SMC1A-DEE loss-of-function (LOF) variants are found exclusively in females due to presumed lethality in males. It is unclear how different SMC1A variants cause CdLS or DEE. Here, we report on phenotypes and genotypes of three females with DEE and de novo SMC1A variants, including a novel splice-site variant. We also summarize 41 known SMC1A-DEE variants to characterize common and patient-specific features. Interestingly, compared to 33 LOFs detected throughout the gene, 7/8 non-LOFs are specifically located in the N/C-terminal ATPase head or the central hinge domain, both of which are predicted to affect cohesin assembly, thus mimicking LOFs. Along with the characterization of X-chromosome inactivation (XCI) and SMC1A transcription, these variants strongly suggest that a differential SMC1A dosage effect of SMC1A-DEE variants is closely associated with the manifestation of DEE phenotypes.

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Novel findings of left ventricular non‐compaction cardiomyopathy, microform cleft lip and poor vision in patient with SMC1A‐associated Cornelia de Lange syndrome

Cited by 14 publications

References 44 publications

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

A novel nonsense SMC1A mutation in a patient with intractable epilepsy and cardiac malformation

Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy

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