Microcephaly Testing

NDE1 sequencing

Mutations in NDE1 [OMIM#609449] were reported in children with severe congenital MIC, with brains smaller than 10 SD below the mean, with simplified gyri, and profound developmental handicap with normal body growth. NDE1 is highly expressed in the developing human and mouse cerebral cortex, particularly at the centrosome, and has a role in mitotic spindle assembly during early neurogenesis. Deficiency of NDE1 therefore appears to cause failure of neurogenesis and a deficiency of cortical lamination.

We also offer mutation analysis of all 8 coding exons and intron/exon boundaries of NDE1 by direct sequencing of amplification products in both the forward and reverse directions.

ASPM deletion/duplication analysis

Autosomal recessive primary microcephaly (MCPH) is characterized by:

congenital microcephaly (3 SD below the mean at birth or at least 4 SD below the mean at later ages)
mental retardation, but no other neurological findings (febrile or other mild seizures do not exclude the diagnosis)
normal or mildly short stature that is less severe than the markedly small head circumference
normal weight and appearance except for the microcephaly

Mutations in the ASPM [OMIM #605481] gene are the most common cause of MCPH. Approximately 40% of patients (both consanguineous and non-consanguineous) with a strict diagnosis of MCPH have mutations in ASPM.

Deletions and/or duplications of the ASPM gene as causative of microcephaly have been reported.

Contact The Foundation for Children with Microcephaly (www.childrenwithmicro.org) for more information and support

WDR62 sequencing

Patients with microcephaly, cortical malformations, and MR have moderate to severe MR and brain malformations including: callosal abnormalities, polymicrogyria, schizencephaly and subcortical heterotopia. Some of these patients have also been described with seizures. This form of MCPH is caused by mutations in the WDR62 gene. Homozygous missense and frameshift mutations were first reported in seven consanguineous families with primary microcephaly and simplified gyri. Like other MCPH genes, WDR62 encodes a spindle pole protein that is expressed in neuronal precursor cells undergoing mitosis in the proliferative phase of neurogenesis.

We offer full gene sequencing of all 30 coding exons of the WDR62 gene.

PNKP sequencing

Autosomal recessive microcephaly, infantile-onset seizures, and developmental delay (MCSZ) is a relatively more severe disorder than autosomal recessive primary microcephaly. Mental retardation is usually severe to profound with variable behavioral problems and seizures are severe and intractable. Mutations in the PNKP gene have been described in seven families with MCSZ. Both homozygous, consanguineous patients and compound heterozygotes were reported.

We offer mutation analysis of all 16 coding exons and intron/exon boundaries of PNKP by direct sequencing of amplification products in both the forward and reverse directions.

Microcephaly tier 2 Panel

Autosomal recessive primary microcephaly (MCPH) is characterized by:

congenital microcephaly (3 SD below the mean at birth or at least 4 SD below the mean at later ages)
mental retardation, but no other neurological findings (febrile or other mild seizures do not exclude the diagnosis)
normal or mildly short stature that is less severe than the markedly small head circumference
normal weight and appearance except for the microcephaly

Mutations in the ASPM gene are the most common cause of MCPH. Approximately 40% of patients (both consanguineous and non-consanguineous) with a strict diagnosis of MCPH have mutations in ASPM.

Several other genes, including CDK5RAP2, CENPJ, MCPH1, STIL, and CEP152 have been reported to cause MCPH in a small number of families.

Homozygous mutations in CDK5RAP2 have been identified in three Pakistani families with MCPH [4,5]. CDK5RAP2 is a centrosomal protein and may be involved in microtubule production during mitosis.
Four Pakistani families with MCPH have been reported with homozygous mutations in CENPJ. CENPJ is a centrosomal protein and likely shares a very similar role with CDK5RAP2.
Homozygous mutations in MCPH1 have been reported in multiple populations, including at least one Pakistani family and at least one Caucasian famil. MCPH1 encodes the Microcephalin protein, which is believed to play a role in cell-cycle timing.
Kumar, et al (2009) reported three Indian families with MCPH that were homozygous for mutations in STIL. STIL is necessary for proper mitotic spindle organization.
Homozygous or compound heterozygous mutations in the CEP152 gene were identified in 3 unrelated Canadian families with MCPH. CEP152 is also a centrosomal protein.

Our MCPH Tier 2 Panel includes full gene sequencing and deletion/duplication analysis for the CDK5RAP2, CENPJ, MCPH1, and STIL genes, along with full gene sequencing of CEP152. Sequencing for these genes cannot be ordered individually.

Contact The Foundation for Children with Microcephaly (www.childrenwithmicro.org) for more information and support.

ASPM sequencing

Autosomal recessive primary microcephaly (MCPH) is characterized by:

congenital microcephaly (3 SD below the mean at birth or at least 4 SD below the mean at later ages)
mental retardation, but no other neurological findings (febrile or other mild seizures do not exclude the diagnosis)
normal or mildly short stature that is less severe than the markedly small head circumference
normal weight and appearance except for the microcephaly

Contact The Foundation for Children with Microcephaly (www.childrenwithmicro.org) for more information and support.

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