Microcephaly

Recommended panel testing at Breda Genetics for this conditions:

Primary microcephaly (MFSD2A, STIL, SASS6, ASPM, KIF14, NCAPH, COPB2, CEP135, WDFY3, CENPE, CDK6, MCPH1, CDK5RAP2, NCAPD3, NCAPD2, PHC1, CIT, ANKLE2, CENPJ, KNL1, CEP152, WDR62, ZNF335)

and/or

Syndromic microcephaly [incl. Seckel syndrome, Meier-Gorlin syndrome, microcephalic dwarfism, lissencephaly and cortical dysplasia, hypomyelinating leukodystrophy, Aicardi-Goutières syndrome, mosaic variegated aneuploidy, Feingold syndrome, Cornelia de Lange syndrome, Smith Lemli Opitz syndrome, Rubinstein-Taybi syndrome, Coffin-Siris syndrome with microcephaly, Neu-Laxova syndrome, Warburg micro syndrome,  Galloway-Mowat syndrome, and others] (TRAIP, CEP63, ATR, NSMCE2, DNA2, CENPJ, NIN, CEP152, RBBP8, ORC1, ORC4, GMNN, ORC6, CDT1, CDC6, CDC45L, MCM5, PCNT, RNU4ATAC, KIF5C, KIF2A, TUBB2A, TUBB2B, TUBB, TUBB3, TUBG1, TUBA8, RELN, LAMB1, CDK5, TUBA1A, TMTC3, NDE1, KATNB1, MDLS, PAFAH1B1, ARX, DCX, ADAR, IFIH1, TREX1, RNASEH2A, RNASEH2C, RNASEH2B, SAMHD1, EPRS, PYCR2, GJC2, HSPD1, AIMP1, RARS, POLR1C, AIMP2, TMEM106B, FAM126A, POL3A, HIKESHI, VPS11, POLR3B, UFM1, TUBB4A, PLP1, ARCN1, ARFGEF2, BRCA1, CASK, CRIPT, DIAPH1, DONSON, EIF2S3, GEMIN4, IER3IP1, KATNB1, KIF11, LIG4, MASP1, MED17, MEIS2, MRE11A, MSMO1, NDE1, NHEJ1, PCDH12, PLAA, PLEKHG2, PLK4, PNKP, PPP1R15B, PRUNE1, QARS, RTTN, SARS, SLC1A4, SLC25A19, STAMPB, THOC6, TRAPPC6B, TRMT10A, TUBGCP4, TUBGCP6, VARS, XRCC2, XRCC4, TRIP13, CEP57, BUB1B, MYCN, MIR17HG, NIPBL, RAD21, SMC3, SMC1A, HDAC8, DHCR7, CREBBP, EP300, DPF2, SMARCE1, SMARCA4, SMARCB1, SMARCA2, PHGDH, PSAT1, RAB3GAP2, RAB3GAP1, RAB18, TBC1D20, TPRKB, OSGEP, WDR73, TP53RK, LAGE2, ZEB2, VPS13B, UBE3B, TRAPPC12, TELO2, SLC2A1, RECQL3, RBBP8, RAD50, PQBP1, NSDHL, CKAP2L, CENPF, C2CD3, OFD1, ATRX, CCDC88A, DCPS, DDX11, EHMT1, OCLN, USP18, NBN, MECP2, KMT2D, KDM6A, FOXG1, ASNS)

and/or

Seckel syndrome (ATR, RBBP8, CENPJ, CEP152, CEP63, NIN, DNA2, TRAIP, NSMCE2)

and/or

Meier Gorlin syndrome and microcephalic primordial dwarfism (ORC1, ORC4, GMNN, ORC6, CDT1, CDC6, CDC45L, MCM5, PCNT, RNU4ATAC)

and/or

Neuronal migration disorders (ACTB, ACTG1, ARFGEF2, ARX, B3GNT1,  B3GALNT2, COL18A1, COL4A1, CPT2, DAG1 , DCX, EMX2, EOMES, ERMARD, FGFR3, FH, FKRP, FKTN, FLNA, GPR56, GTDC2, IER3IP1, ISPD, KIF2A, KIF5C, LAMA2, LAMC3, LARGE1, MED12, MEF2C, NEDD4L, OCLN, PAFAH1B1, PAX6, PEX7, POMGNT1, POMK, POMT1, POMT2, PQBP1, RAB18, RAB3GAP1, RAB3GAP2, RELN, SHH, SIX3, SNAP29, SRPX2, TBC1D20, TMEM5, TUBA1A, TUBA8, TUBB, TUBB2A, TUBB2B, TUBB3, TUBG1, USP18,  VLDLR, WDR62)

and/or

Lissencephaly (ARX, CDK5, DCX, NDE1, KATNB1, LAMB1, PAFAH1B1, POMT1, POMT2, RELN, TUBA1A)

and/or

Cortical dysplasia and lissencephaly (KIF5C, KIF2A, TUBB2A, TUBB2B, TUBB, TUBB3, TUBG1, TUBA8, RELN, LAMB1, CDK5, TUBA1A, TMTC3, NDE1, KATNB1, MDLS, PAFAH1B1, ARX, DCX)

and/or

Pontocerebellar hypoplasia, extended (AMPD2, CASK, CHMP1A, CLP1, COASY, EXOSC3, EXOSC8, EXOSC9, KIF26B, PCLO, RARS2, SEPSECS, SLC25A46, TBC1D23, TOE1, TSEN15, TSEN2, TSEN34, TSEN54, VPS53, VRK1)

and/or

Epileptic encephalopathy (ACY1, ADSL, ALDH7A1, AMT, ARHGEF9, ARX, CDKL5, CNTNAP2, CPT2, FOLR1, FOXG1, GABRG2, GAMT, GCSH, GLDC, GRIN2A, GRIN2B, KCNJ10, KCNQ2, MAGI2, MAPK10, MECP2, MTHFR, NRXN1, PCDH19, PLCB1, PNKP, PNPO, PRRT2, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SLC25A22, SLC2A1, SLC9A6, SPTAN1, STXBP1, TBCE, TCF4, TREX1, UBE3A, ZEB2)

Summary

Microcephaly (MC) is diagnosed when the occipito-frontal circumference (OFC) is more than 2 standard deviations (SD) below the average for age- and gender-matched healthy individuals. Severe MC is diagnosed when the OFC is 3 SD below the mean. OFC measures the skull size, but it’s used most widely as a proxy for brain volume. Reduced OFC has a relevant clinical connotation as being considered a sign of brain underdevelopment, which in turns constitutes a risk factor for cognitive and motor delay.

MC can be observed prenatally or at birth (congenital or primary MC), or develop later in life (post-natal or secondary MC). Prenatal and neonatal MC is mainly associated to reduced neurogenesis or death of neuronal progenitors in the earliest phases of cortical development. By contrast, postnatal MC is often degenerative and predominantly associated to defects in brain maturation rather than brain formation. However, many conditions may be characterized by components of both prenatal and postnatal MC.  MC can be an isolated finding (non-syndromic MC) or part of a complex syndrome (syndromic MC).

Detailed clinical description

In patients with severe congenital MC (primary MC), the brain continues to grow after birth but at a much slower pace than usual, resulting in a consistent worsening of the OFC over time. Patients with secondary MC are usually born with normal to slightly reduced OFC and develop MC progressively in the postnatal development. A sloping forehead is often noticed, especially in cases with a severe reduction of the OFC.

Non-syndromic MC exclusively affects cerebral development, although other intracranial abnormalities correlating with the abnormal development of the cerebral cortex may be present. The typical finding is that of a small brain with a grossly preserved organization and shape of the gyri, which may show mild to significantly simplified pattern. Since the volume of the underlying neuropil (glial processes, axons, dendrites, etc.) is dependent on the number of neurons and glial cells, also the white matter is usually reduced. Some individuals may show reduced size of the corpus callosum or the hindbrain (pons and cerebellum). Secondary features may be caused by assocaited neuronal migration defects, leading to lissencephaly, pachigyria, polymicrogyria or subcortical band heterotopia. Cognitive impairment in microcephalic patients ranges from mild to severe. In general, individuals with severe MC tend to have additional brain abnormalities and severe neurodevelopmental impairment (PMID: 20301772, PMID: 22427329).

Common findings in syndromic MC include facial dysmorphism, neurological disorders, visceral and/or skeletal malformations, metabolic dysfunction, and other cogenital defects.

Prevalence

Congenital MC is a rare condition. Reliable data on its prevalence is limited and highly variable according to the inclusion criteria employed. Birth defects registries report incidence of severe MC (including stillbirths and terminated pregnancies) ranging from 0.5/10,000 to 10-20/10,000 births (WHO 2016). The European Surveillance of Congenital Anomalies (EUROCAT) estimated the prevalence of MC in Europe to be 2 per 10,000 (including both environmental and genetic etiology), which compares with reported prevalences of 1.98 per 10,000 in Brazil (before the Zika virus epidemic), 2.3 per 10,000 in India, and 6.0 per 10,000 in the US (PMID: 27623840). It has been estimated that genetic conditions account for about 30% of all individuals diagnosed with severe MC (PMID: 24617602). Comparably to other neurodevelopmental disorders, highly inbred populations and genetic isolates are usually characterized by a higher incidence of individuals affected by rare recessive MC disorders.

Molecular genetics

MC may be caused by a wide range of genetic defects, from chromosomal abnormalities (e.g. contigous gene syndromes) to point mutations in one single gene (monogenic disorders). Chromosomal aberrations may be private (i.e. found for the first time in that patient or family) or recurrent in the population. Examples of well known recurrent chromosomal abnormalities include Wolf-Hirshhorn syndrome (4p16.3 deletion), Miller-Dieker syndrome (17p13.3 deletion), 1p36 deletion, and 1q41-q42 deletion. In certain contiguous gene syndromes, the gene causing the microcephalic trait has been isolated (e.g. the KCTD13 gene, which has been isolated in the 16p11.2 microdeletion/duplication syndrome).

For what concerns monogenic disorders, there is a recognized group of non-syndromic primary MC forms resulting in severe MC (< 3SDs) and intellectual disability, usually without other clinical findings. These disorders are known as “microcephalia vera” or “primary hereditary microcephaly” (MCPH). A group of 23 genes is currently associated to MCPH (PS251200). All genes are associated to autosomal recessive inheritance, with a single exception of autosomal dominant inheritance (WDFY3). Almost all these genes encode for proteins involved in key steps of the cell replication machinery, including DNA replication and checkpoint activation (MCPH1, CASC5), chromosome condensation (NCAPH, NCAPD2, NCAPD3), centriole duplication (STIL, CENPJ, SASS6), microtubule dynamics (KIF14), spindle generation and positioning (ASPM, CDK5RAP2), kinetochore attachment (CENPE, CASC5) and cytokinesis/midbody clearance (CIT/WDFY3). Some genes act as trancriptional regulators via chromatin binding and remodeling (PHC1, ZNF335). An important exception to this pattern is represented by the MFSD2A gene, which encodes for a sodium-dependent lysophosphatidylcholine (LPC) symporter localized in the endothelium of the blood-brain-barrier (PMID: 30086807, PMID: 28399591).

Coming to syndromic MC, we’ll recall here below some of the most common ones, highlighting that MC may be a constant or inconstant trait in hundreds of genetic conditions.

Microcephaly can be found in patients with syndromes due to defects in DNA damage repair genes such as Fanconi anemia, Bloom syndrome, Nijmegen breakage syndrome, Warsaw breakage syndrome, Xeroderma pigmentosum, Cockayne syndrome,  or LIG4 syndrome (PMID: 18458003, PMID: 24816482). These disorders are characterized by other main features such as growth failure, immunodeficiency and/or high predisposition to cancer, or abnormal skin pigmentation.

Microcephaly can be accompanied by a range of ocular anomalies in syndromes characterized by both MC and chorioretinopathy. These patients show delayed psychomotor development ranging from mild to profound, seizures, and ocular anomalies such as corioretinopathy, retinal dystrophy, cataract, and visual impairment. Bi-allelic mutations in TUBGCP6, PLK4, and TUBGCP4 have been linked to these syndromes. Patients with heterozygous mutations in KIF11, on the other hand, present a syndrome of MC accompanied by variable developmental delay, congenital lymphedema usually confined to the dorsa of the feet, and ocular anomalies, including chorioretinopathy, retinal folds, cataract, microphtalmia, and microcornea.  In Warburg micro syndrome, ocular abnormalities are peculiar, but patients also show other brain malformations (e.g. cerebellar atrophy, hypoplastic corpus callosum, polymicrogyria), neurologic disfunction (hypotonia, progressive spasticity, seizures), hypogonadism, and joint contractures. Bi-allelic mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20 may cause Warburg micro syndrome.

MC can be also associated to impaired glucose metabolism leading to early onset insulin dependent diabetes, severe intellectual disability, and hypoglycemic seizures. Mutations in  the PPP1R15B, IER3IP1 or TRMT10A genes may cause this autosomal recessive syndromes.

Osteodysplastic types of microcephalic dwarfism (MOPD) include MOPD1, which is caused by mutations in the RNU4ATAC gene, and MOPD2, which is caused by mutations in the PCNT gene. Both disorders are autosomal recessively inherited. Individuals with microcephalic osteodysplastic primordial dwarfism (MOPD) are characterized by intrauterine and postnatal growth retardation, disproportionate short stature due to short limbs, and generalized skeletal abnormalities such as long clavicles, short and bowed long bones, dislocation of elbows and hips, and delayed bone age. MOPD1 is a more severe condition compared to MOPD2 , the latter being characterized by preserved or mildly reduced intellect (PMID: 26323792).

Another type of osteodysplastic primordial dwarfism is Meier-Gorlin syndrome (MGORS), charaterized by pre- and post-natal growth retardation, typical facial dysmorphism such as microtia, mid-face hypoplasia, aplasia or hypoplasia of the patellae, and skeletal anomalies. Despite MC, intellectual development is usually preserved. MGORS is caused by bi-allelic mutations in the following genes: ORC1, ORC4, ORC6, GMNN, or MCM5 (PMID: 26323792).

Differential diagnosis

MCPH shows clinical and genetic overlap with Seckel syndrome (SCKLS), a rare autosomal recessive type of non-osteodysplastic primordial dwarfism characterized by a typical “bird-like” facies with prominent beaked nose. The two disorders were once distinguished by stature, since SCKLS patients are characterized by intrauterine and post-natal growth retardation and are generally much shorter than MCPH patients. However, short stature is no longer considered a discriminating factor, since mutations in MCPH genes have been identified also in  some SCKLS cases. Hence, these conditions should be better considered a clinical continuum rather than distinct entities. The genes of which mutations cause Seckel syndrome are: ATR, RBBP8, CENPJ, CEP152, CEP63, NIN, DNA2, TRAIP, and NSMCE2.

Genetic testing strategy

Given the extreme clinical and genetic heterogenity of syndromic and non-syndromic microcephaly, we recommend considering different NGS panels for step-wise testing. Breda Genetics panels based on whole exome or whole genome sequencing repesent the ideal solution for microcephaly testing, as they allow fast and flexible tier testing and, when necessary, the upgrade to full data analysis.

Recommended panel testing at Breda Genetics for this conditions:

Primary microcephaly (MFSD2A, STIL, SASS6, ASPM, KIF14, NCAPH, COPB2, CEP135, WDFY3, CENPE, CDK6, MCPH1, CDK5RAP2, NCAPD3, NCAPD2, PHC1, CIT, ANKLE2, CENPJ, KNL1, CEP152, WDR62, ZNF335)

and/or

Syndromic microcephaly [incl. Seckel syndrome, Meier-Gorlin syndrome, microcephalic dwarfism, lissencephaly and cortical dysplasia, hypomyelinating leukodystrophy, Aicardi-Goutières syndrome, mosaic variegated aneuploidy, Feingold syndrome, Cornelia de Lange syndrome, Smith Lemli Opitz syndrome, Rubinstein-Taybi syndrome, Coffin-Siris syndrome with microcephaly, Neu-Laxova syndrome, Warburg micro syndrome,  Galloway-Mowat syndrome, and others] (TRAIP, CEP63, ATR, NSMCE2, DNA2, CENPJ, NIN, CEP152, RBBP8, ORC1, ORC4, GMNN, ORC6, CDT1, CDC6, CDC45L, MCM5, PCNT, RNU4ATAC, KIF5C, KIF2A, TUBB2A, TUBB2B, TUBB, TUBB3, TUBG1, TUBA8, RELN, LAMB1, CDK5, TUBA1A, TMTC3, NDE1, KATNB1, MDLS, PAFAH1B1, ARX, DCX, ADAR, IFIH1, TREX1, RNASEH2A, RNASEH2C, RNASEH2B, SAMHD1, EPRS, PYCR2, GJC2, HSPD1, AIMP1, RARS, POLR1C, AIMP2, TMEM106B, FAM126A, POL3A, HIKESHI, VPS11, POLR3B, UFM1, TUBB4A, PLP1, ARCN1, ARFGEF2, BRCA1, CASK, CRIPT, DIAPH1, DONSON, EIF2S3, GEMIN4, IER3IP1, KATNB1, KIF11, LIG4, MASP1, MED17, MEIS2, MRE11A, MSMO1, NDE1, NHEJ1, PCDH12, PLAA, PLEKHG2, PLK4, PNKP, PPP1R15B, PRUNE1, QARS, RTTN, SARS, SLC1A4, SLC25A19, STAMPB, THOC6, TRAPPC6B, TRMT10A, TUBGCP4, TUBGCP6, VARS, XRCC2, XRCC4, TRIP13, CEP57, BUB1B, MYCN, MIR17HG, NIPBL, RAD21, SMC3, SMC1A, HDAC8, DHCR7, CREBBP, EP300, DPF2, SMARCE1, SMARCA4, SMARCB1, SMARCA2, PHGDH, PSAT1, RAB3GAP2, RAB3GAP1, RAB18, TBC1D20, TPRKB, OSGEP, WDR73, TP53RK, LAGE2, ZEB2, VPS13B, UBE3B, TRAPPC12, TELO2, SLC2A1, RECQL3, RBBP8, RAD50, PQBP1, NSDHL, CKAP2L, CENPF, C2CD3, OFD1, ATRX, CCDC88A, DCPS, DDX11, EHMT1, OCLN, USP18, NBN, MECP2, KMT2D, KDM6A, FOXG1, ASNS)

and/or

Seckel syndrome (ATR, RBBP8, CENPJ, CEP152, CEP63, NIN, DNA2, TRAIP, NSMCE2)

and/or

Meier Gorlin syndrome and microcephalic primordial dwarfism (ORC1, ORC4, GMNN, ORC6, CDT1, CDC6, CDC45L, MCM5, PCNT, RNU4ATAC)

and/or

Neuronal migration disorders (ACTB, ACTG1, ARFGEF2, ARX, B3GNT1,  B3GALNT2, COL18A1, COL4A1, CPT2, DAG1 , DCX, EMX2, EOMES, ERMARD, FGFR3, FH, FKRP, FKTN, FLNA, GPR56, GTDC2, IER3IP1, ISPD, KIF2A, KIF5C, LAMA2, LAMC3, LARGE1, MED12, MEF2C, NEDD4L, OCLN, PAFAH1B1, PAX6, PEX7, POMGNT1, POMK, POMT1, POMT2, PQBP1, RAB18, RAB3GAP1, RAB3GAP2, RELN, SHH, SIX3, SNAP29, SRPX2, TBC1D20, TMEM5, TUBA1A, TUBA8, TUBB, TUBB2A, TUBB2B, TUBB3, TUBG1, USP18,  VLDLR, WDR62)

and/or

Lissencephaly (ARX, CDK5, DCX, NDE1, KATNB1, LAMB1, PAFAH1B1, POMT1, POMT2, RELN, TUBA1A)

and/or

Cortical dysplasia and lissencephaly (KIF5C, KIF2A, TUBB2A, TUBB2B, TUBB, TUBB3, TUBG1, TUBA8, RELN, LAMB1, CDK5, TUBA1A, TMTC3, NDE1, KATNB1, MDLS, PAFAH1B1, ARX, DCX)

and/or

Pontocerebellar hypoplasia, extended (AMPD2, CASK, CHMP1A, CLP1, COASY, EXOSC3, EXOSC8, EXOSC9, KIF26B, PCLO, RARS2, SEPSECS, SLC25A46, TBC1D23, TOE1, TSEN15, TSEN2, TSEN34, TSEN54, VPS53, VRK1)

and/or

Epileptic encephalopathy (ACY1, ADSL, ALDH7A1, AMT, ARHGEF9, ARX, CDKL5, CNTNAP2, CPT2, FOLR1, FOXG1, GABRG2, GAMT, GCSH, GLDC, GRIN2A, GRIN2B, KCNJ10, KCNQ2, MAGI2, MAPK10, MECP2, MTHFR, NRXN1, PCDH19, PLCB1, PNKP, PNPO, PRRT2, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SLC25A22, SLC2A1, SLC9A6, SPTAN1, STXBP1, TBCE, TCF4, TREX1, UBE3A, ZEB2)

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