ORPHA: 199; DO: 0080507;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q25.2 | Cornelia de Lange syndrome 3 | 610759 | Autosomal dominant | 3 | SMC3 | 606062 |
A number sign (#) is used with this entry because of evidence that Cornelia de Lange syndrome-3 with or without midline brain defects (CDLS3) is caused by heterozygous mutation in the SMC3 gene (606062) on chromosome 10q25.
Cornelia de Lange syndrome is a multisystem developmental disorder characterized by distinctive facial dysmorphism, pre- and postnatal growth failure, delayed psychomotor development and impaired intellectual development, hypertrichosis, and sometimes distal limb malformations (summary by Gil-Rodriguez et al., 2015).
For a phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see 122470.
Deardorff et al. (2007) identified a patient with a mild form of Cornelia de Lange syndrome who carried a mutation in the SMC3 gene. The patient had arched eyebrows, synophrys, and long eyelashes, thin lips, small hands and feet, proximally set thumbs, fifth finger clinodactyly, restriction of elbow movements, and hirsutism, in addition to high nasal bridge and high palate. He lacked brachycephaly, low anterior hairline, anteverted nostrils, long philtrum, downturned corners of the mouth, micrognathia, and hearing loss. He was employed in a supervised position in a greenhouse. The authors noted that both SMC3 and SMC1A (300040) mutation-positive patients exhibit mild facial dysmorphism, no absence or reduction of limbs or digits, and no other major structural anomalies.
Gil-Rodriguez et al. (2015) reported the clinical features of 16 patients with CDLS3 confirmed by genetic analysis, including the patient reported by Deardorff et al. (2007) and 5 patients reported by Ansari et al. (2014). Many patients had CDLS-like craniofacial features, although severe features were typically infrequent or absent. Features included brachycephaly (11/15), low anterior hairline (7/14), arched eyebrows (14/15), synophrys (11/15), long eyelashes (15/16), ptosis (4/15), depressed nasal bridge (7/15), anteverted nostrils (8/14), long philtrum (10/15), thin upper lip vermilion (13/16), downturned corners of the mouth (9/15), high palate (5/11), dental anomalies (5/13), and micrognathia (6/15). Although often long, the philtrum is typically not smooth in these individuals and only 1 patient had a cleft palate. Major limb malformations were not observed. Intellectual disability was a prominent feature, although behavioral problems were not frequently reported and many were described as having friendly personalities. Cardiac malformations occurred in about 56%, and many had some degree of pulmonic stenosis. Additional highly variable features included gastroesophageal reflux, cutis marmorata, short neck, micrognathia, and restriction of elbow movements, among others.
Clinical Variability
Kruszka et al. (2019) reported a male fetus with a severe form of CDLS3. He had semilobar holoprosencephaly, cleft lip, tetralogy of Fallot, cutaneous syndactyly of the hands and feet, hypospadias, and anal atresia. The findings expanded the phenotype associated with mutations in the SMC3 gene.
In patients with CDLS3 for whom parental DNA was available, the heterozygous mutations in the SMC3 gene that were identified by Deardorff et al. (2007) and Ansari et al. (2014) occurred de novo.
The patient identified by Deardorff et al. (2007) with a mild form of CDLS carried a de novo heterozygous 3-bp deletion in the SMC3 gene (606062.0001). Deardorff et al. (2007) noted that the milder CDLS phenotype had been reported repeatedly and accounts for approximately 20 to 30% of the CDLS population. The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of CDLS, resulting in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, and in some instances, resulted in a phenotype that approaches that of apparently nonsyndromic mental retardation.
In 5 unrelated patients with CDLS3, Ansari et al. (2014) identified 5 different heterozygous mutations in the SMC3 gene (see, e.g., 606062.0002 and 606062.0003). The mutations were shown to occur de novo in those with available parental DNA. Functional studies were not performed, and clinical details of the patients were not provided. The patients were ascertained from a larger cohort of 163 individuals who underwent genetic analysis for CDLS mutations, and thus accounted for 3.1% of the larger group.
Gil-Rodriguez et al. (2015) identified heterozygous mutations in the SMC3 gene (see, e.g., 606062.0001; 606062.0004-606062.0008) in 10 unrelated patients with CDLS3. The mutations were shown to occur de novo in those with available parental DNA. The mutations were found by either gene panel sequencing or exome sequencing, and none were found in 100 control alleles of publicly available databases; functional studies were not performed. Based on their studies and previous reports, Gil-Rodriguez et al. (2015) estimated that SMC3 mutations account for about 1 to 2% of patients with features of CDLS.
In a male fetus with a severe form of CDLS3 with midline brain defects manifest as semilobar holoprosencephaly, Kruszka et al. (2019) identified a de novo heterozygous 15-bp in-frame deletion in the SMC3 gene (606062.0009). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function (LOF). The authors noted that the SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database.
Ansari, M., Poke, G., Ferry, Q., Williamson, K., Aldridge, R., Meynert, A. M., Bengani, H., Chan, C. Y., Kayserili, H., Avci, S., Hennekam, R. C. M., Lampe, A. K., and 63 others. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J. Med. Genet. 51: 659-668, 2014. [PubMed: 25125236] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102573]
Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Am. J. Hum. Genet. 80: 485-494, 2007. [PubMed: 17273969] [Full Text: https://doi.org/10.1086/511888]
Gil-Rodriguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., Ousager, L. B., Puisac, B., Hernandez-Marcos, M., Teresa-Rodrigo, M. E., Marcos-Alcalde, I., Wesselink, J.-J. and 50 others. De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes. Hum. Mutat. 36: 454-462, 2015. [PubMed: 25655089] [Full Text: https://doi.org/10.1002/humu.22761]
Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. Cohesin complex-associated holoprosencephaly. Brain 142: 2631-2643, 2019. [PubMed: 31334757] [Full Text: https://doi.org/10.1093/brain/awz210]