ORPHA: 199; DO: 0080508;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.11 | Cornelia de Lange syndrome 4 | 614701 | Autosomal dominant | 3 | RAD21 | 606462 |
A number sign (#) is used with this entry because Cornelia de Lange syndrome-4 with or without midline brain defects (CDLS4) is caused by heterozygous mutation in the RAD21 gene (606462), which encodes a component of the cohesin complex, on chromosome 8q24.
For a phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see CDLS (122470).
Deardorff et al. (2012) reported 2 unrelated patients, a boy and a girl, with a phenotype suggestive of Cornelia de Lange syndrome. Both had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long or prominent eyelashes, broad nasal bridge, smooth philtrum, and thin upper lip. The boy had ptosis and an upturned nasal tip, whereas the girl had upslanted palpebral fissures and a short nose. The boy had a number of additional congenital anomalies, including poor dental enamel, submucosal cleft palate, stapes fixation, thin fingers, left radioulnar synostosis, delayed skeletal age, vertebral clefting, pectus carinatum, short femoral neck, tetralogy of Fallot, intestinal malrotation, and gastroesophageal reflux. He also had severe cognitive delay and attention deficit-hyperactivity disorder. The girl had short fingers, fifth finger clinodactyly, small prominent first toe, long fourth metacarpal, cutis marmorata, and mild neurodevelopmental defects.
Kruszka et al. (2019) reported 3 unrelated patients (patients 12-14) with CDLS4 ascertained from a larger cohort of patients with holoprosencephaly (HPE) who underwent exome sequencing. The patients had classic features of CDLS, including developmental delay, microcephaly, brachycephaly, hypo- or hypertelorism, synophrys, long philtrum, upturned or short nose, low-set ears, thin vermilion border, and cleft palate. One patient had seizures and another had small hands, fifth finger clinodactyly, and gastroesophageal reflux. Brain imaging showed variable midline brain defects, including HPE, MIHV (middle interhemispheric variant of HPE), and septooptic dysplasia. The father of one of the patients, who also carried the mutation, had synophrys and a submucosal cleft palate; brain imaging of the father was not reported. Kruszka et al. (2019) noted that the incidence of midline brain defects in patients with CDLS may be higher than originally thought, since not all patients undergo brain imaging.
Goel and Parasivam (2020) described a female fetus who was found to have mild unilateral ventriculomegaly on prenatal ultrasound and on prenatal MRI at 24 weeks' gestation. At 32 weeks' gestation, a repeat MRI found lobar holoprosencephaly with fusion of the occipital horns of the lateral ventricles across the midline and an absent posterior septum. After pregnancy termination at 34 weeks' gestation, the infant was found to have hypertelorism, flat face, broad nasal bridge, long and flat philtrum, and thin lips.
Boyle et al. (2017) reported a 26-year-old woman with microcephaly, learning disabilities, and facial features of CDLS including synophrys, high-arched and thick eyebrows, long philtrum, and anteverted nares. Her mother had similar but milder features. Two maternal aunts (patients III:1 and III:2) had low anterior and posterior hairlines, short and broad necks, bilateral limited elbow extension, learning disabilities, and hearing loss. Patient III:2 also had a cleft palate and mild structural heart disease. Patient III:1 was diagnosed with osteoporosis at 25 years of age. None of the patients had behavioral symptoms of CDLS.
Minor et al. (2014) reported 3 patients, including a mother and son, with CDLS4. Patient 1 was a boy with a history of developmental delay, severe hypospadias, inguinal hernia, dysmorphic features, congenital nystagmus, strabismus, and unilateral ptosis. At age 3 years he was able to speak 4- or 5-word phrases and had autistic features. On examination, he had scaphocephaly, coarse facial features, frontal bossing, mild synophrys, unilateral ptosis, and micrognathia. His affected 42-year-old mother had a history of myopia, obsessive-compulsive tendencies, anxiety, and depression. Facial features included a long face, high nasal bridge, tooth crowding, and thick eyebrows. Patient 2 was a boy with developmental delay, dysmorphic facial features, hirsutism, and hand anomalies. He received special education for reading disabilities and attention deficit-hyperactivity disorder (ADHD). On physical examination at age 12 years, he had microcephaly, brachycephaly, thick bushy eyebrows with synophrys, a bilateral transverse palmar crease, syndactyly of the second and third fingers, and fifth finger clinodactyly.
Dorval et al. (2020) reported a boy with CDLS4 who had a history of progressive microcephaly. Cognitive testing at age 5 years showed a heterogeneous intellectual profile with verbal IQ in the low average range for age, performance IQ in the average range, and an extremely low processing speed.
Gudmundsson et al. (2019) reported a patient with CDLS4 who had left-sided congenital diaphragmatic hernia, which was surgically repaired 2 days after birth. At 15 months of age he had growth delay and microcephaly, prominent digital finger pads, and a single transverse palmar crease.
Krab et al. (2020) performed a literature review, database search, and review of identified but unreported patients with RAD21 mutations and CDLS4. Clinical features were reported in 29 patients from 22 families, with an age range of 0 to 61 years and a median age of 9 years. About half of these patients had congenital anomalies, including cleft palate and cardiac anomalies. Major limb defects were not seen, and hands and feet were not small. Most children were able to attend regular education or received education for children with mild cognitive disabilities. Behavioral problems, including anxiety, ADHD, and autism spectrum disorder, were seen in most patients. There was no observed correlation between the severity of cognitive impairment and the presence of microcephaly.
The transmission pattern of CDLS4 in a family reported by Kruszka et al. (2019) was consistent with autosomal dominant inheritance with possible incomplete penetrance of some of the features.
Deardorff et al. (2012) reported 4 unrelated patients with a complex phenotype most reminiscent of Cornelia de Lange syndrome associated with a heterozygous deletion of chromosome 8q24. Two of the patients had previously been reported by Wuyts et al. (2002) and McBrien et al. (2008), respectively. The patient reported by Wuyts et al. (2002) had mild mental retardation, complex partial seizures, multiple exostoses, hypertrichosis, and striking facial features, including small head, thick eyebrows with synophrys, telecanthus, downward slanting palpebral fissures, broad nose, long philtrum, and thin upper lip. FISH and SNP analysis detected a de novo interstitial deletion of 8q24 including the EXT1 gene (608177), but not the TRPS1 gene (190350). The patient reported by McBrien et al. (2008) had low birth weight, talipes calcaneovalgus, persistent fetal toe pads, microcephaly, and bifid scrotum. He was dysmorphic, with microcephaly, prominent eyebrows, long eyelashes, thin upper lip, and sparse, fine scalp hair. Other features included cutis marmorata, hemivertebrae, exostoses, and borderline developmental delay. Oligoarray CGH showed a 1.46-Mb deletion of 8q24.11 including the EXT1 gene, but not the TRPS1 gene. The phenotype in both of these patients was suggestive of Langer-Giedion syndrome (150230). The 2 patients first reported by Deardorff et al. (2012) had short stature, microcephaly, thick eyebrows, long eyelashes, broad nasal bridge, and exostoses. One patient had additional features, such as cutis marmorata, coxa vara, long fourth metacarpal, cleft palate, and micrognathia, but normal cognition. The other patient had delayed development. Both patients had interstitial deletions of 8q24 encompassing several genes, including RAD21.
In 2 unrelated patients with Cornelia de Lange syndrome-4, Deardorff et al. (2012) identified different de novo heterozygous mutations in the RAD21 gene (P376R, 606462.0001 and C585R, 606462.0002). These mutations were identified by screening of the RAD21 gene in 258 individuals with a CDLS-like phenotype after genomewide copy-number analysis had identified a different patient with a de novo deletion of chromosome 8q24.1 that included RAD21. In vitro studies showed that the P376R mutation resulted in altered activity of the mutant protein rather than a loss of function. Patient cells showed decreased sister chromatid separation, increased aneuploidy, and defective DNA repair, as well as abnormal transcriptional activity in a zebrafish model. The boy with the P376R mutation had a more severe phenotype than the girl with the C585R mutation. Functional studies of the C585R mutation suggested a loss of function, similar to patients with deletion of the RAD21 gene. Deardorff et al. (2012) concluded that dominant RAD21 mutations result in more severe functional defects and a worse phenotype than loss-of-function mutations or deletions. Deardorff et al. (2012) also noted that RAD21 lies between TRPS1 and EXT1, and would thus be deleted in persons with Langer-Giedion syndrome. The mild facial and cognitive involvement seen in individuals with RAD21 heterozygous loss-of-function (LOF) mutations may cause many individuals to go clinically unnoticed.
In 3 unrelated patients with CDLS4 with midline brain defects in the HPE spectrum, Kruszka et al. (2019) identified heterozygous frameshift or nonsense mutations in the RAD21 gene (606462.0004-606462.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were identified from a cohort of over 277 HPE patients who underwent exome sequencing. All of the mutations were predicted to result in a loss of function, although functional studies of the variants and studies of patient cells were not performed. A father of one of the patients with milder symptoms also carried the heterozygous mutation; the inheritance pattern of the other 2 patients was unknown. The authors noted that the RAD21 gene is intolerant to LOF variation based on data from gnomAD.
Goel and Parasivam (2020) identified a de novo heterozygous nonsense mutation in the RAD21 gene (E615X; 606462.0007) in a female fetus with CDLS4 and lobar holoprosencephaly. The mutation was identified by clinical exome analysis of 4,702 genes. Functional studies were not performed.
In a 26-year-old woman with mild CDLS4, Boyle et al. (2017) identified a heterozygous mutation in the RAD21 gene (606462.0008). The woman's mother and 2 maternal aunts, who were also heterozygous for the mutation, had variable, milder features seen in CDLS4 but did not meet clinical criteria for the disorder. Boyle et al. (2017) concluded that the intrafamilial phenotypic variation suggested incomplete penetrance.
In a mother and son and an unrelated patient with CDLS4, Minor et al. (2014) identified heterozygous mutations in the RAD21 gene (606462.0009 and 606462.0010, respectively).
In a 5-year-old boy with CDLS4, Dorval et al. (2020) identified a de novo heterozygous frameshift mutation in the RAD21 gene (606462.0011).
In a 15-month-old boy with CDLS4, Gudmundsson et al. (2019) identified a de novo heterozygous mutation in the RAD21 gene (606462.0012). Molecular modeling predicted that the mutation disrupted the interaction of RAD21 with SMC1A (300040).
Krab et al. (2020) examined clinical and molecular data in 29 patients from 22 families with CDLS4. There was a higher trend in CDLS clinical scores and more frequently impaired growth parameters in patients with microdeletions involving RAD21 compared to patients with intragenic mutations. A comparison of the clinical features in this cohort with RAD21 mutations to those in patients with CDLS2 (300590) due to mutations in SMC1A (300040) or CDLS1 (122470) due to mutations in NIPBL (608667) showed that patients with RAD21 mutations had overall less impaired growth at birth, short stature, and postnatal microcephaly as well as lower prevalence and decreased severity of impaired intellectual development.
Boyle, M. I., Jespersgaard, C., Nazaryan, L., Bisgaard, A.-M., Tumer, Z. A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome--review of the literature. (Letter) Clin. Genet. 91: 647-649, 2017. [PubMed: 27882533] [Full Text: https://doi.org/10.1111/cge.12863]
Deardorff, M. A., Wilde, J. J., Albrecht, M., Dickinson, E., Tennstedt, S., Braunholz, D., Monnich, M., Yan, Y., Xu, W., Gil-Rodriguez, M. C., Clark, D., Hakonarson, H., and 15 others. RAD21 mutations cause a human cohesinopathy. Am. J. Hum. Genet. 90: 1014-1027, 2012. [PubMed: 22633399] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.019]
Dorval, S. Masciadri, M., Mathot, M., Russo, S., Revencu, N., Larizza, L. A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: further delineation of the phenotype. Europ. J. Med. Genet. 63: 103620, 2020. [PubMed: 30716475] [Full Text: https://doi.org/10.1016/j.ejmg.2019.01.010]
Goel, H., Parasivam, G. Another case of holoprosencephaly associated with RAD21 loss-of-function variant. (Letter) Brain 143: e64, 2020. Note: Electronic Article. [PubMed: 32696056] [Full Text: https://doi.org/10.1093/brain/awaa173]
Gudmundsson, S., Anneren, G., Marcos-Alcalde, I., Wilbe, M., Melin, M., Gomez-Puertas, P., Bondeson, M.-L. A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4--review of the literature. Europ. J. Med. Genet. 62: 103526, 2019. [PubMed: 30125677] [Full Text: https://doi.org/10.1016/j.ejmg.2018.08.007]
Krab, L. C., Marcos-Alcalde, I., Assaf, M., Balasubramanian, M., Andersen, J. B., Bisgaard, A.-M., Fitzpatrick, D. R., Gudmundsson, S., Huisman, S. A., Kalayci, T., Maas, S. M., Martinez, F., and 14 others. Delineation of phenotypes and genotypes related to cohesin structural protein RAD21. Hum. Genet. 139: 575-592, 2020. [PubMed: 32193685] [Full Text: https://doi.org/10.1007/s00439-020-02138-2]
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]
McBrien, J., Crolla, J. A., Huang, S., Kelleher, J., Gleeson, J., Lynch, S. A. Further case of microdeletion of 8q24 with phenotype overlapping Langer-Giedion without TRPS1 deletion. Am. J. Med. Genet. 146A: 1587-1592, 2008. [PubMed: 18478595] [Full Text: https://doi.org/10.1002/ajmg.a.32347]
Minor, A., Shinawi, M., Hogue, J. S., Vineyard, M., Hamlin, D. R., Tan, C., Donato, K., Wysinger, L., Botes, S., Das, S., del Gaudio, D. Two novel RAD 21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene 537: 279-284, 2014. [PubMed: 24378232] [Full Text: https://doi.org/10.1016/j.gene.2013.12.045]
Wuyts, W., Roland, D., Ludecke, H.-J., Wauters, J., Foulon, M., Van Hul, W., Van Maldergem, L. Multiple exostoses, mental retardation, hypertrichosis, and brain abnormalities in a boy with a de novo 8q24 submicroscopic interstitial deletion. Am. J. Med. Genet. 113: 326-332, 2002. [PubMed: 12457403] [Full Text: https://doi.org/10.1002/ajmg.10845]