ORPHA: 2512; DO: 0070280;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q31.3 | Microcephaly 5, primary, autosomal recessive | 608716 | Autosomal recessive | 3 | ASPM | 605481 |
A number sign (#) is used with this entry because primary microcephaly-5 (MCPH5) is caused by homozygous or compound heterozygous mutation in the ASPM gene (605481) on chromosome 1q31.
Autosomal recessive primary microcephaly-5 (MCPH5) is characterized by decreased occipitofrontal circumference (OFC), usually less than 3 standard deviations (SD) of the mean, present at birth and associated with mental retardation and speech delay. Other features may include short stature or mild seizures. MCPH5 is associated with a simplification of the cerebral cortical gyral pattern in some cases, which is considered within the phenotypic spectrum of primary microcephaly (review by Woods et al., 2005; Saadi et al., 2009; Passemard et al., 2009).
For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly (MCPH), see MCPH1 (251200).
Pattison et al. (2000) performed DNA analysis on 3 living individuals in separate sibships related as cousins in a consanguineous Pakistani family with primary microcephaly showing linkage to chromosome 1q31. All were microcephalic from birth with head circumferences between -5 and -7 SD from the norm when they were examined at ages 4, 7, and 28 years. All had moderate mental retardation with no apparent diminution of abilities with age. They were all in good health and not dysmorphic; with the exception of minor language delay, they had normal developmental milestones. All were affable, followed instructions well, and had learned good self-help skills. The parents had normal intelligence and head circumference.
Shen et al. (2005) identified homozygosity for a mutation in the ASPM gene (605481.0008) in 3 sibs with primary microcephaly from a consanguineous family from Saudi Arabia. Two of the sibs had frequent seizures and the other had no seizures. Shen et al. (2005) suggested that a history of seizures should not preclude the diagnosis of primary microcephaly.
Desir et al. (2008) reported a girl, born of consanguineous Moroccan parents, with microcephaly (-3.5 SD), delayed language, and 2 seizure episodes at age 4 years. Brain MRI showed a simplified gyral pattern, more severe in the frontal lobes, with decreasing severity toward the parietal and temporal regions. At age 6, she had hyperactivity and an IQ of 50. Fetal sonography of a second pregnancy in this family showed recurrence of microcephaly. Fetal brain MRI at 30 weeks' gestation showed decreased cortical gyri in an anterior to posterior gradient. The frontal lobes were small and squared off.
Saadi et al. (2009) reported a consanguineous Algerian family in which 3 of 5 sibs had primary microcephaly. All had low to low-normal birth weight, variable speech impairment, and mental retardation. Brain MRI showed severe hypoplasia of the frontal lobes, moderate posterior parietal atrophy, an anterior orientation of the insula, a thick corpus callosum, and global gyral simplification. Despite the parental consanguinity, genetic analysis identified compound heterozygous mutations in the ASPM gene (605481.0010 and 605481.0011).
Passemard et al. (2009) reported 11 probands and 5 sibs with MCPH5 confirmed by genetic analysis. Microcephaly was severe after age 1 year of age in all 16 patients, although 4 patients had OFC that were only 2 SD below the mean at birth. All had borderline-normal to severe mental retardation and delayed speech development. Other clinical features included late-onset seizures in 3 patients and pyramidal tract involvement in 1. Seven patients had mild motor delay. Among 12 patients with brain MRI, 9 had a simplified gyral pattern, 7 had enlarged ventricles, 3 had partial agenesis of the corpus callosum, 1 had mild cerebellar hypoplasia, 1 had focal cortical dysplasia, and 1 had unilateral polymicrogyria. Passemard et al. (2009) noted that the phenotype in their patients was more heterogeneous than previously described: some patients had low-normal OFC at birth followed by a decrease with age, and some had IQ values in the 70 to 80 range. The gradual OFC decline noted in the study had not been highlighted previously. Brain MRI indicated that microcephaly with simplified gyration (603802) may be part of the ASPM phenotypic spectrum. In addition, the study showed for the first time that loss of ASPM function can be associated with cortical defects. Cortical dysgenesis has not been reported previously in MCPH, possibly because this finding would have led to patient exclusion. These findings significantly expanded the phenotype associated with mutations in the ASPM gene.
Darvish et al. (2010) found that affected members of 3 consanguineous Iranian families with MCPH5 due to ASPM nonsense mutations also had short stature; congenital hearing loss was an additional feature in 1 of these families.
Abdel-Hamid et al. (2016) reported 21 patients from 15 unrelated Egyptian families with MCPH5 confirmed by genetic analysis. The patients had a small head (-3.6 to -12 SD) with bitemporal narrowing, as well prominent eyes, arched eyebrows, and a prominent glabella. These facial features became more subtle with age. Brain imaging showed small frontal lobe and simplified gyral pattern in all patients, but with variable severity. Other common features included hypoplasia of the corpus callosum (85.7%), enlarged ventricles (90.5%), small pons (61.9%), and small cerebellar vermis (47.6%). Five patients had short stature, 4 had growth retardation, and 2 had seizures.
The transmission pattern of MCPH5 in the families reported by Abdel-Hamid et al. (2016) was consistent with autosomal recessive inheritance.
Perez-Castillo et al. (1984) suggested that true microcephaly may result from a mutation at the 1q31-q32 junction. They observed microcephaly in a proband with a reciprocal translocation between 1q and 4p. The mother and other maternal relatives over at least 4 generations had the rearrangement. They suggested that the father was heterozygous for a microcephaly mutation at a locus corresponding to the breakpoint in chromosome 1, giving rise to the rearrangement. Their reason for selecting chromosome 1 rather than 4 as the site of the abnormality was the observation of Ferguson-Smith (1981), reported as a personal communication in the 1983 edition of Mendelian Inheritance in Man, of a child with severe microcephaly and deletion of 1q25-q32 whose parents were normal and unrelated.
Although the microcephalic proband reported by Perez-Castillo et al. (1984) had been lost to follow-up, Pichon et al. (2004) reexamined the translocation breakpoint in this family by sampling a maternal aunt who carried the apparently balanced t(1;4)(q31;p15.3) translocation. By FISH analyses, Pichon et al. (2004) located the translocation breakpoint within intron 17 of the ASPM gene, which results in a predicted protein truncated of more than half of the primary sequence. The authors noted that the translocation segregated in at least 5 asymptomatic subjects over 3 generations, consistent with recessivity and indicative of a mutation in the paternal allele of the proband. Pichon et al. (2004) stated that this was the second example of an autosomal recessive disease associated with gene disruption by a reciprocal translocation.
In a family of Turkish origin, Jamieson et al. (2000) used homozygosity mapping to assign a locus for autosomal recessive primary microcephaly, MCPH5, to chromosome 1q25-q32. The maximum multipoint lod score was 3.51 at marker D1S1723. The minimal critical region spanned 11.4 cM between markers D1S384 and D1S2655, and encompassed the cytogenetic breakpoint in chromosomal aberrations previously reported in unrelated patients with microcephaly.
Simultaneously and independently, in a consanguineous Pakistani family, Pattison et al. (2000) determined by linkage mapping that an MCPH locus is located on chromosome 1q31.
In each of 4 consanguineous northern Pakistani families with primary microcephaly, Bond et al. (2002) identified a homozygous mutation introducing a premature stop codon into the predicted ASPM open reading frame (605481.0001-605481.0004). Bond et al. (2002) were unable to distinguish phenotypically between the 4 families in which these mutations were found.
Bond et al. (2003) performed a comprehensive mutation screen of the ASPM gene and identified 19 mutations in a cohort of 23 consanguineous families. The mutations occurred throughout the gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5 to 11 SDs below normal) and of mental retardation (mild to severe) but appeared to be independent of mutation position in the gene.
MCPH5 accounted for 43% (24 of 56) of MCPH families in the northern Pakistani population studied by Roberts et al. (1999, 2002).
Gul et al. (2006) identified 6 different mutations in the ASPM gene in affected members of 9 unrelated consanguineous Pakistani families with MCPH.
In 2 sibs, born of consanguineous Moroccan parents, with MCPH5 and simplified gyral pattern on brain MRI, Desir et al. (2008) identified a homozygous truncating mutation in the ASPM gene (605481.0009). The data indicated that at least 1 form of primary microcephaly is allelic to a form of microcephaly with simplified gyral pattern (603802). However, Desir et al. (2008) noted that prenatal and postnatal brain imaging of patients with microcephaly has rarely been reported, suggesting that the 2 disorders may actually represent a phenotypic continuum.
Nicholas et al. (2009) sequenced the ASPM gene in 3 cohorts of microcephalic children. Pathogenic ASPM mutations were identified in 39% of 99 consanguineous MCPH families, and in 11 (40%) of 27 nonconsanguineous predominantly Caucasian families with a strict diagnosis of MCPH. In contrast, only 3 (7%) of 45 families with a less restricted phenotype, including microcephaly and mental retardation, had an ASPM mutation. Some of the patients with mutations had seizures. Overall, the report identified 27 novel mutations in the ASPM gene, which almost doubled the number of MCPH-associated ASPM mutations. All but 1 of the mutations resulted in premature termination. There were no definitive missense mutations and no genotype/phenotype correlations. Nicholas et al. (2009) concluded that ASPM mutations are the most common cause of strict MCPH.
Muhammad et al. (2009) identified homozygous ASPM mutations in 20 Pakistani families with microcephaly and compound heterozygous ASPM mutations in 2 Pakistani families with microcephaly, yielding a mutation detection rate of 59.5% (22 of 37 families). A total of 16 different nonsense or frameshift mutations, including 12 novel mutations, were identified, increasing the number of reported ASPM mutations from 35 to 47. There was no correlation between the severity of the condition and the site of mutation.
Passemard et al. (2009) identified homozygous or compound heterozygous mutations in the ASPM gene in 11 (22%) of 52 probands with microcephaly. Sixteen novel mutations were identified, and all 18 mutations were truncating or nonsense mutations.
Among 112 consanguineous Iranian families with primary microcephaly, Darvish et al. (2010) found that 13 (14.1%) showed linkage to the MCPH5 locus. However, homozygous mutations in the ASPM gene were only found in 11 families. One mutation had previously been reported by Nicholas et al. (2009), and 10 novel mutations were identified, 9 of which were predicted to result in a truncated protein.
Sajid Hussain et al. (2013) found linkage to 5 different MCPH disease loci in 34 of 57 consanguineous Pakistani families with autosomal recessive primary microcephaly. Pathogenic mutations were found in 27 of the 34 families. Eighteen families showed linkage to the ASPM gene, and pathogenic mutations were found in 17 families. ASPM was the most commonly mutated gene: the W1326X mutation (605481.0006) was present in 8 families, suggesting a founder effect. The second most commonly mutated gene was WDR62 (613583), consistent with MCPH2 (604317), found in 5 families.
Abdel-Hamid et al. (2016) identified 13 truncating mutations in the ASPM gene in 21 patients from 15 (50%) of 30 unrelated Egyptian families with autosomal recessive primary microcephaly who underwent screening of the ASPM gene. The mutations were homozygous or compound heterozygous in the patients and segregated with the disorder in all families. Two mutations (R1327X and R3181X) were recurrent, and could be considered founder mutations in this population. Functional studies of the variant and studies of patient cells were not performed.
Abdel-Hamid, M. S., Ismail, M. F., Darwish, H. A., Effat, L. K., Zaki, M. S., Abdel-Salam, G. M. H. Molecular and phenotypic spectrum of ASPM-related primary microcephaly: identification of eight novel mutations. Am. J. Med. Genet. 170A: 2133-2140, 2016. [PubMed: 27250695] [Full Text: https://doi.org/10.1002/ajmg.a.37724]
Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. ASPM is a major determinant of cerebral cortical size. Nature Genet. 32: 316-320, 2002. [PubMed: 12355089] [Full Text: https://doi.org/10.1038/ng995]
Bond, J., Scott, S., Hampshire, D. J., Springell, K., Corry, P., Abramowicz, M. J., Mochida, G. H., Hennekam, R. C. M., Maher, E. R., Fryns, J.-P., Alswaid, A., Jafri, H., Rashid, Y., Mubaidin, A., Walsh, C. A., Roberts, E., Woods, C. G. Protein-truncating mutations in ASPM cause variable reduction in brain size. Am. J. Hum. Genet. 73: 1170-1177, 2003. [PubMed: 14574646] [Full Text: https://doi.org/10.1086/379085]
Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. A clinical and molecular genetic study of 112 Iranian families with primary microcephaly. J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014. [PubMed: 20978018] [Full Text: https://doi.org/10.1136/jmg.2009.076398]
Desir, J., Cassart, M., David, P., Van Bogaert, P., Abramowicz, M. Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally. Am. J. Med. Genet. 146A: 1439-1443, 2008. [PubMed: 18452193] [Full Text: https://doi.org/10.1002/ajmg.a.32312]
Ferguson-Smith, M. A. Personal Communication. Glasgow, Scotland 7/9/1981.
Gul, A., Hassan, M. J., Mahmood, S., Chen, W., Rahmani, S., Naseer, M. I., Dellefave, L., Muhammad, N., Rafiq, M. A., Ansar, M., Chishti, M. S., Ali, G., Siddique, T., Ahmad, W. Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene. Neurogenetics 7: 105-110, 2006. [PubMed: 16673149] [Full Text: https://doi.org/10.1007/s10048-006-0042-4]
Jamieson, C. R., Fryns, J.-P., Jacobs, J., Matthijs, G., Abramowicz, M. J. Primary autosomal recessive microcephaly: MCPH5 maps to 1q25-q32. Am. J. Hum. Genet. 67: 1575-1577, 2000. [PubMed: 11067780] [Full Text: https://doi.org/10.1086/316909]
Muhammad, F., Mahmood Baig, S., Hansen, L., Hussain, M. S., Inayat, I. A., Aslam, M., Qureshi, J. A., Toilat, M., Kirst, E., Wajid, M., Nurnberg, P., Eiberg, H., Tommerup, N., Kjaer, K. W. Compound heterozygous ASPM mutations in Pakistani MCPH families. Am. J. Med. Genet. 149A: 926-930, 2009. [PubMed: 19353628] [Full Text: https://doi.org/10.1002/ajmg.a.32749]
Nicholas, A. K., Swanson, E. A., Cox, J. J., Karbani, G., Malik, S., Springell, K., Hampshire, D., Ahmed, M., Bond, J., Di Benedetto, D., Fichera, M., Romano, C., Dobyns, W. B., Woods, C. G. The molecular landscape of ASPM mutations in primary microcephaly. J. Med. Genet. 46: 249-253, 2009. [PubMed: 19028728] [Full Text: https://doi.org/10.1136/jmg.2008.062380]
Passemard, S., Titomanlio, L., Elmaleh, M., Afenjar, A., Alessandri, J.-L., Andria, G., Billette de Villemeur, T., Boespflug-Tanguy, O., Burglen, L., Del Giudice, E., Guimiot, F., Hyon, C., and 11 others. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology 73: 962-969, 2009. [PubMed: 19770472] [Full Text: https://doi.org/10.1212/WNL.0b013e3181b8799a]
Pattison, L., Crow, Y. J., Deeble, V. J., Jackson, A. P., Jafri, H., Rashid, Y., Roberts, E., Woods, C. G. A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31. Am. J. Hum. Genet. 67: 1578-1580, 2000. [PubMed: 11078481] [Full Text: https://doi.org/10.1086/316910]
Perez-Castillo, A., Martin-Lucas, M. A., Abrisqueta, J. A. Is a gene for microcephaly located on chromosome 1? Hum. Genet. 67: 230-232, 1984. [PubMed: 6745946] [Full Text: https://doi.org/10.1007/BF00273009]
Pichon, B., Vankerckhove, S., Bourrouillou, G., Duprez, L., Abramowicz, M. J. A translocation breakpoint disrupts the ASPM gene in a patient with primary microcephaly. Europ. J. Hum. Genet. 12: 419-421, 2004. [PubMed: 14997185] [Full Text: https://doi.org/10.1038/sj.ejhg.5201169]
Roberts, E., Hampshire, D. J., Pattison, L., Springell, K., Jafri, H., Corry, P., Mannon, J., Rashid, Y., Crow, Y., Bond, J., Woods, C. G. Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J. Med. Genet. 39: 718-721, 2002. [PubMed: 12362027] [Full Text: https://doi.org/10.1136/jmg.39.10.718]
Roberts, E., Jackson, A. P., Carradice, A. C., Deeble, V. J., Mannan, J., Rashid, Y., Jafri, H., McHale, D. P., Markham, A. F., Lench, N. J., Woods, C. G. The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1-13.2. Europ. J. Hum. Genet. 7: 815-820, 1999. [PubMed: 10573015] [Full Text: https://doi.org/10.1038/sj.ejhg.5200385]
Saadi, A., Borck, G., Boddaert, N., Chekkour, M. C., Imessaoudene, B., Munnich, A., Colleaux, L., Chaouch, M. Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family. Europ. J. Med. Genet. 52: 180-184, 2009. [PubMed: 19332161] [Full Text: https://doi.org/10.1016/j.ejmg.2009.03.013]
Sajid Hussain, M., Marriam Bakhtiar, S., Farooq, M., Anjum, I., Janzen, E., Reza Toliat, M., Eiberg, H., Kjaer, K. W., Tommerup, N., Noegel, A. A., Nurnberg, P., Baig, S. M., Hansen, L. Genetic heterogeneity in Pakistani microcephaly families. Clin. Genet. 83: 446-451, 2013. [PubMed: 22775483] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01932.x]
Shen, J., Eyaid, W., Mochida, G. H., Al-Moayyad, F., Bodell, A., Woods, C. G., Walsh, C. A. ASPM mutation identified in patients with primary microcephaly and seizures. (Letter) J. Med. Genet. 42: 725-729, 2005. [PubMed: 16141009] [Full Text: https://doi.org/10.1136/jmg.2004.027706]
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]