ORPHA: 2512; DO: 0070291;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q15.1 | Microcephaly 4, primary, autosomal recessive | 604321 | Autosomal recessive | 3 | KNL1 | 609173 |
A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-4 (MCPH4) is caused by homozygous mutation in the CASC5 gene (KNL1; 609173) on chromosome 15q15.
Primary microcephaly (MCPH) is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations below the age- and sex-matched population mean and mental retardation, with no other associated malformations and with no apparent etiology. Most cases of primary microcephaly show an autosomal recessive mode of inheritance (summary by Woods et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Jamieson et al. (1999) reported 4 sibs, born of consanguineous Moroccan parents, with primary microcephaly (head circumference -5 to -6 SD). The patients also had poor overall growth and mental retardation. Brain CT scan of the proband showed enlarged ventricles, but no other abnormalities.
Genin et al. (2012) provided follow-up of the family reported by Jamieson et al. (1999) and reported 2 additional similarly affected families. All were consanguineous and of Moroccan origin from small villages about 50 km apart. All patients had head circumferences of -4 to -7 SD and mild to moderate mental retardation. Stature and motor development was normal; none had seizures or neurologic deficits.
Saadi et al. (2016) described 4 sibs in a consanguineous Algerian family with primary microcephaly. Low head circumference at birth was noted by the parents. Psychomotor development was delayed, with all affected individuals starting to walk at the age of 18 months and showing reduced verbal fluency, only producing a few words. At the age of 23 to 29 years, the patients had marked speech delay and moderate to severe cognitive deficit. They were unable to write, read, count or confirm their ages. Two had difficulty eating, walking, and dressing independently. All had a sloping forehead, thick eyebrows, synophrys, and low columella. Head circumferences ranged from -3 to -4 SD below the mean for age and gender, and all had short stature. Cerebral MRI in 2 sibs showed a small brain, shortened frontal lobe, dilated occipital horns, and cerebellar vermis hypoplasia in one, and only a small brain in the other.
Zarate et al. (2016) reported an African American male infant with primary microcephaly. At birth, the boy weighed 3.08 kg, was 49.5 cm long, and had an OFC of 31.1 cm. While his length and weight measurements fluctuated between low-for-age and normal during the first year of life, his OFC was consistently below -3 SD for age. An MRI at 7 months of age showed simplified gyral pattern and a very mild delay of myelination. At 17 months of age, he had severe microcephaly (-4.88 SD) but had achieved normal milestones.
The transmission pattern of primary microcephaly in the family reported by Jamieson et al. (1999) was consistent with autosomal recessive inheritance.
Jamieson et al. (1999) reported homozygosity mapping of a novel locus, which they termed MCPH4, at 15q15-q21 in a consanguineous Moroccan family with primary microcephaly. By homozygosity mapping of the family reported by Jamieson et al. (1999), Genin et al. (2012) narrowed the candidate region to a 3.7-Mb interval at 15q14-q15, which excluded the CEP152 gene (613529).
By homozygosity mapping followed by candidate gene sequencing in 3 Moroccan families with primary microcephaly, including the family originally reported by Jamieson et al. (1999), Genin et al. (2012) identified a homozygous missense mutation (M2041I; 609173.0001) in the CASC5 gene (609173.0001). None of the patients had a mutation in the CEP152 gene. Haplotype analysis indicated a founder effect. The mutation was predicted to inactivate an exonic splicing enhancer, and was demonstrated to result in abnormal splicing and production of a transcript lacking exon 18 and causing premature termination. However, normal CASC5 protein levels were also found in patient lymphoblastoid cells. Patient lymphoblasts showed no abnormalities in mitosis, no changes in growth rate, and no micronuclei. Immunofluorescence studies showed no defects of CASC5 expression in patient fibroblasts, and mitotic spindles were normal. None of the patients developed leukemia, consistent with normal CASC5 function in nonneurologic cells. Although this mutant CASC5 appeared to function normally in patient lymphoblasts and fibroblasts, Genin et al. (2012) speculated that it may express the defect only in neural cells.
In affected members of a consanguineous Algerian family with primary microcephaly, Saadi et al. (2016) identified homozygosity for the same M2041I mutation in the CASC5 gene that had been identified by Genin et al. (2012) in Moroccan families. Haplotype analysis supported the existence of a common ancestor.
In an African American male infant with primary microcephaly, Zarate et al. (2016) identified compound heterozygosity for a de novo frameshift (609173.0002) mutation and a maternally inherited missense (D2178G; 609173.0003) mutation in the CASC5 gene. The frameshift mutation was not found in the dbSNP, Exome Variant Server, or ExAC databases; the D2178G mutation was present in the ExAC database at a low frequency in the general population, but primarily in patients of African ancestry, with a heterozygous minor allele frequency of 0.0034 in that population.
Exclusion Studies
Genin et al. (2012) directly sequenced the CASC5 gene in a cohort of patients with primary microcephaly, including 3 probands from consanguineous families with homozygosity at the MCPH4 locus, and did not find any additional mutations, suggesting that CASC5 mutations are a rare cause of microcephaly.
Although MCPH4 was originally thought to be due to mutation in the CEP152 gene on chromosome 15q21 based on the report of Guernsey et al. (2010), Genin et al. (2012) later identified a mutation in the CASC5 gene on 15q14 in the original family with MCPH4 (Jamieson et al., 1999). Microcephaly caused by mutation in the CEP152 gene is now designated MCPH9 (614852), and microcephaly caused by mutation in the CASC5 gene is now designated MCPH4.
Genin, A., Desir, J., Lambert, N., Biervliet, M., Van Der Aa, N., Pierquin, G., Killian, A., Tosi, M., Urbina, M., Lefort, A., Libert, F., Pirson, I., Abramowicz, M. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum. Molec. Genet. 21: 5306-5317, 2012. [PubMed: 22983954] [Full Text: https://doi.org/10.1093/hmg/dds386]
Guernsey, D. L., Jiang, H., Hussin, J., Arnold, M., Bouyakdan, K., Perry, S., Babineau-Sturk, T., Beis, J., Dumas, N., Evans, S. C., Ferguson, M., Matsuoka, M., and 12 others. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am. J. Hum. Genet. 87: 40-51, 2010. [PubMed: 20598275] [Full Text: https://doi.org/10.1016/j.ajhg.2010.06.003]
Jamieson, C. R., Govaerts, C., Abramowicz, M. J. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. (Letter) Am. J. Hum. Genet. 65: 1465-1469, 1999. [PubMed: 10521316] [Full Text: https://doi.org/10.1086/302640]
Saadi, A., Verny, F., Siquier-Pernet, K., Bole-Feysot, C., Nitschke, P., Munnich, A., Abada-Dendib, M., Chaouch, M., Abramowicz, M., Colleaux, L. Refining the phenotype associated with CASC5 mutation. Neurogenetics 17: 71-78, 2016. [PubMed: 26626498] [Full Text: https://doi.org/10.1007/s10048-015-0468-7]
Woods, C. G., Bond, J., Enard, W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am. J. Hum. Genet. 76: 717-728, 2005. [PubMed: 15806441] [Full Text: https://doi.org/10.1086/429930]
Zarate, Y. A., Kaylor, J. A., Bosanko, K., Lau, S., Vargas, J., Gao, H. First clinical report of an infant with microcephaly and CASC5 mutations. (Letter) Am. J. Med. Genet. 170A: 2215-2218, 2016. [PubMed: 27149178] [Full Text: https://doi.org/10.1002/ajmg.a.37726]