Microcephaly Panel

Overview

Microcephaly Panel

Establish or confirm diagnosis

Missense and frameshift mutations were identified in two Turkish families with autosomal recessive periventricular heterotopia with microcephaly [OMIM#608097] which is characterized by microcephaly, periventricular heterotopia, intellectual disability and recurrent infections. A homozygous mutation in ATR was been identified in two consanguineous Pakistani families with Seckel syndrome [OMIM#210600]. Seckel syndrome is characterized by severe proportionally short stature with severe microcephaly, a ‘bird like’ profile including a beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and intellectual disability. Mutations in ATRX are associated with a wide and clinically heterogeneous spectrum of X-linked mental retardation syndromes. Clinical features may include intellectual disability, hypotonia, microcephaly, genital abnormalities, short stature and seizures. Affected individuals may have microcytic hypochromic anemia characteristic of alpha-thalassemia, however many do not. Carrier females are typically not affected. X-linked mental retardation and microcephaly with pontine and cerebellar hypoplasia (MIC-PHC) [OMIM #300749] is associated with de novo CASK mutations, and is characterized by severe or profound intellectual disability, microcephaly, and disproportionate pontine and cerebellar hypoplasia in females. Mutations associated with MIC-PHC are believed to be lethal in males, however milder familial mutations may also be observed, which can cause intellectual disability in males. A homozygous nonsense mutation was identified in CEP63 in a consanguineous family of Pakistani descent with three members with primary microcephaly and proportionate short stature, clinically consistent with mild Seckel syndrome [OMIM#614728]. A homozygous missense mutation was identified in 5 infants from 4 Jewish families with postnatal progressive microcephaly and severe developmental retardation associated with cerebral and cerebellar atrophy. Mutations in NDE1 have been reported in children with severe congenital microcephaly, with brains smaller than 10 SD below the mean, simplified gyri, and profound intellectual disability. Homozygous mutations have been reported in one Turkish, two Saudi and two Pakistani consanguineous families. Mutations in PCNT have been identified in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II) [OMIM#210720]. MOPD II is characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly. Rauch et al. (2008) identified 29 different homozygous or compound heterozygous mutations in the PCNT gene in 25 patients with MOPD2. Mutations in the PNKP gene have been described in seven families with autosomal recessive microcephaly, infantile-onset seizures, and developmental delay (MCSZ) [OMIM#613402]. Both homozygous and compound heterozygous mutations have been reported. In patients with MCSZ, intellectual disability is usually severe to profound with variable behavioral problems and severe and intractable seizures. A homozygous splicing mutation in RBBP8 was identified in four siblings affected by Seckel syndrome [OMIM#606744] in a consanguinous Iraqi family. Seckel syndrome is characterized by severe proportionally short stature with severe microcephaly, a ‘bird like’ profile including a beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and intellectual disability. Amish lethal microcephaly [OMIM#607196] is characterized by the presence of microcephaly and a tenfold increase in the levels of urinary organic acid 2-ketoglutarate. To date, all affected individuals within the Old Order Amish population (in which the prevalence of this condition in this population is approximately 1 in 500 births) are homozygous for a founder mutation in SLC25A19. McDonnell et al. identified mutations in STAMBP in a cohort of patients with Microcephaly-Capillary malformation (MIC-CAP) syndrome [OMIM#606247]. MIC-CAP is characterized by small scattered capillary malformations, congenital microcephaly, early-onset intractable epilepsy, profound global developmental delay, spastic quardriparesis, hypoplastic distal phalanges and poor growth. Mutations in ZEB2 are associated with Mowat-Wilson syndrome (MWS) [OMIM # 235730], which is characterized by distinctive facial features, moderate-to-severe mental retardation, microcephaly and seizures. Microcephaly may be either congenital or acquired postnatally. Congenital anomalies are also common, including Hirschsprung disease, genitourinary anomalies, congenital heart defects, agenesis of the corpus callosum and eye anomalies. Mutations in the ASPM gene are the most common cause of autosomal recessive primary microcephaly. Approximately 40% of patients with a strict diagnosis of MCPH have mutations in ASPM. However, fewer patients (<10%) with a less restrictive phenotype have mutations in ASPM. Genin et al. (2012) identified the same CASC5 frameshift mutation in the homozygous state in three separate consanguineous families with autosomal recessive primary microcephaly. Homozygous mutations in CDK5RAP2 have been identified in three Pakistani families with autosomal recessive primary microcephaly. Four Pakistani families with autosomal recessive primary microcephaly have been reported with homozygous mutations in CENPJ. Hussain et al. identified a homozygous frameshift mutation in a consanguineous family with two siblings affected by autosomal recessive primary microcephaly. Homozygous or compound heterozygous mutations in the CEP152 gene were identified in 3 unrelated Canadian families with MCPH. Homozygous mutations in MCPH1 have been reported in multiple populations, including at least one Pakistani family and at least one Caucasian family. Kumar et al (2009) reported three Indian families with autosomal recessive primary microcephaly that were homozygous for mutations in STIL. Mutations in WDR62 have been reported in a subset of patients with microcephaly, cortical malformations, and moderate to severe ID. In addition to microcephaly, these patients also have various brain malformations including callosal abnormalities, polymicrogyria, schizencephaly and subcortical nodular heterotopia. A subset have seizures. Homozygous missense and frameshift mutations were first reported in seven consanguineous families. Yang et al. (2012) identified a homozygous mutation in ZNF335 in a large consanguineous Arab-Israeli family with severe autosomal recessive primary microcephaly. CDKL5 mutations have been described in females X-linked infantile spasms [OMIM#300672], which is associated with early-onset refractory epilepsy, severe developmental delay, absent or limited speech, in addition to postnatal microcephaly and hand stereotypies in some patients. Mutations in males are associated with a more severe phenotype of early-onset tonic and myoclonic seizures, intractable infantile spasms, severe global developmental delay, cortical visual impairment and sleep disturbances. Abnormalities of the FOXG1 gene have been identified in patients with the congenital variant of Rett syndrome [OMIM#613454]. Patients with FOXG1 mutations typically have early onset epilepsy, severe cognitive impairment, progressive postnatal microcephaly, postnatal growth deficiency and dyskinetic movement disorders. Unlike classic Rett syndrome there is typically no observed period of normal development prior to onset of symptoms. MECP2 mutations are present in 70-90% of females with classic Rett syndrome [OMIM#312750] and approximately 20% of females with atypical Rett syndrome. Classic Rett syndrome is a progressive disorder characterized by acquired microcephaly, epilepsy, poor growth, loss of purposeful hand movements, and autistic behaviors, following a period of normal growth and development. MECP2 mutations appear to be more common in females than in males, and the majority of cases are de novo. There have been reports of unaffected or mildly affected MECP2 carrier females due to skewed X inactivation. A homozygous missense mutation in MED17 was identified in 5 infants from 4 Jewish families with postnatal progressive microcephaly with seizures and brain atrophy [OMIM#613668]. Mutations in RAB18, RAB3GAP1 and RAB3GAP2 are associated with Warburg Micro syndrome [OMIM#600118], which is characterized by ocular and neurodevelopmental abnormalities and hypothalamic hypogonadism. Key clinical features include microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia and atrophy, congenital hypotonia, severe intellectual disability, and spastic diplegia. Brain magnetic resonance imaging (MRI) of affected individuals consistently shows polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, thin corpus callosum and increased subdural spaces. Glucose transporter-1 (GLUT-1) deficiency syndrome [OMIM#612126] is caused by mutations in the SLC2A1 gene, which lead to impaired glucose transport in the brain. The classic GLUT-1 deficiency syndrome presentation is drug-resistant infantile-onset seizures, acquired microcephaly, developmental delay, hypotonia, spasticity, ataxia and dystonia. A ketogenic diet is effective in mitigating clinical findings in affected individuals. Mutations in the SLC9A6 gene have been identified in patients with X-linked Angelman-like syndrome [OMIM#300243]. Features of males with SLC9A6 mutations include progressive microcephaly, grand mal epilepsy, lack of speech, trunal ataxia, excessive drooling, and a happy demeanor with spontaneous smiling and laughter. Mutations in SLC9A6 result in clinical features in affected males and occasionally some mild features in carrier females. Mutations in TCF4 are associated with Pitt-Hopkins syndrome (PHS) [OMIM#610954]. PHS is characterized by severe mental retardation and dysmorphic facial features, which tend to coarsen with age. Other common features include acquired microcephaly, epilepsy, hyperventilation episodes, short stature, stereotypic hand movements, and absent speech. Mutations in UBE3A are one of the causes of Angelman syndrome [OMIM#105830], which is characterized by severe intellectual disability, frequent laughing/smiling, easy excitability, and severe speech impairment. Other characteristics noted in over 80% of patients include microcephaly, seizures, and a specific, abnormal EEG pattern. Most mutations in UBE3A are de novo, with a <1% recurrence rate, however some cases may be familial.

• Clinical Testing/Confirmation of Mutations Identified Previously
• Confirmation of research findings
• Custom Prenatal Testing
• Custom mutation-specific/Carrier testing