Autosomal Recessive Primary Microcephaly

Last update 08 May 2025

Basic Info

Synonyms

Autosomal Recessive Primary Microcephaly, Autosomal recessive primary microcephaly, Autosomal recessive primary microcephaly (disorder)

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Introduction

Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development with features of reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment. It is more common in specific populations, e.g. northern Pakistanis. Consanguinity appears to play a role in incidence. Patients have a reduction in head circumference at birth of at least 2 standard deviations below ethnically matched, age- and sex-related mean values. Caused by mutations in MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, STIL, CEP63, CEP135 , CASC5 and PHC1. These mutations appear to lead to reduced generation of cerebral cortical neurons during embryonic neurogenesis. Inheritance is autosomal recessive.

Clinical Trials associated with Autosomal Recessive Primary Microcephaly

NCT01565005

/ CompletedNot ApplicableIIT

Microcephaly Genetic Deficiency in Neural Progenitors: Genotyping, Phenotyping and Functional Neuro-anatomy and Neurobiology Comparative Primitive Microcephaly (MCPH) and the Fanconi Anemia (FA)

The purpose of this study is to:
I. Compare neuroradiological phenotype and cognitive functioning of MCPH patients caused by ASPM mutations already characterized and published (Passemard et al. 2009a) with other MCPH-related patients (patients with MCPH1, WDR62, CDK5RAP2, CEP 152, CENPJ, STIL, or PCNT mutations)
II. Describe the neuro-radiological and cognitive phenotype of microcephalic patients suffering from Fanconi anemia, and compared them to subjects with:
Fanconi anemia but normal OFC (head circumference)
MCPH patients
Healthy control subjects Our hypothesis is that mutations in genes responsible of microcephaly impact differentially cortical brain development and functioning

Start Date01 Oct 2013

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

100 Clinical Results associated with Autosomal Recessive Primary Microcephaly

100 Translational Medicine associated with Autosomal Recessive Primary Microcephaly

0 Patents (Medical) associated with Autosomal Recessive Primary Microcephaly

326

Literatures (Medical) associated with Autosomal Recessive Primary Microcephaly

01 Dec 2024·Molecular Biology Reports

Investigating the effects of a single ASPM variant (c.8508_8509) on brain architecture among siblings in a consanguineous Pakistani family

Article

Author: Khan, Ramisha ; Saeed, Aysha ; Bashir, Rasheeda ; Makhdoom, Ehtisham Ul Haq ; Jamil, Iffat ; Rafiq, Shereen ; Hussain, Muhammad Sajid ; Anjum, Iram ; Aslam, Komal ; Hassan, Samina ; Baig, Shahid Mahmood ; Asif, Maria ; Saeed, Hafiza Iqra

BACKGROUNDAutosomal Recessive Primary Microcephaly (MCPH) is a rare, neurodevelopmental disorder associated with mild to severe mental retardation. It is characterized by reduced cerebral cortex that ultimately leads to reduction in skull size less than - 3 S.D below the mean for normal individuals having same age and sex. Till date, 30 known loci have been reported for MCPH.METHODSIn the present study, Sanger sequencing was performed followed by linkage analysis to validate the mutation in ASPM gene of the consanguineous Pakistani clans. Bioinformatics tools were also used to confirm the pathogenicity of the diseased variant in the gene. MRI scan was used to compare the brain structure of both the affected individuals (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023).RESULTSOur study described a consanguineous family with two patients with a known ASPM (MCPH5) variant c.8508_8509delGA causing a frameshift mutation in exon 18 which located in calmodulin-binding IQ domain of the ASPM protein. The salient feature of this study is that a single variant led to significantly distinct changes in the architecture of brain of both siblings which is further confirmed by MRI results. The computation analysis showed that the change in the conservation of this residue cause this variant highly pathogenic. Carrier screening and genetic counselling were also remarkable features of this study (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023).CONCLUSIONThis study explores the extraordinary influence of a single ASPM variant on divergent brain structure in consanguineous siblings and enable us to reduce the incidence of further microcephalic cases in this Pakistani family (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023).

01 Dec 2024·Molecular Biology Reports

Second report of TEDC1-related microcephaly caused by a novel biallelic mutation in an Iranian consanguineous family

Article

Author: Rezaie, Nahid ; Vaghefi, Fatemeh ; Al Sudani, Zainab Mohammed ; Khosravi, Teymoor ; Oladnabi, Morteza ; Sarli, Abdolazim ; Motallebi, Farzaneh

BACKGROUNDPrimary autosomal recessive microcephaly (MCPH) is a rare developmental disorder characterized by cognitive impairment, delayed neurodevelopment, and reduced brain size. It is a genetically heterogeneous condition, and several genes have been identified as associated with MCPH.METHODS AND RESULTSIn this study, we utilized whole-exome sequencing (WES) to identify disease-causing variations in two brothers from an Iranian family affected by MCPH, who had consanguineous parents. In the patients, we detected a novel homozygous missense mutation (c.806A > G, p.Gln269Arg) in the TEDC1 gene in one of the patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from parents. The identified variant was evaluated for its pathogenicity and novelty using various databases. Additionally, bioinformatics tools were employed to predict the three-dimensional structure of the mutant TEDC1 protein.CONCLUSIONSThis study presents the second documented report of a mutation in the TEDC1 gene associated with MCPH. The identification of this novel biallelic mutation as a causative factor for MCPH in the proband further underscores the utility of genetic testing techniques, such as WES, as reliable diagnostic tools for individuals with this condition.

01 Dec 2024·Molecular Biology Reports

Molecular genetics, neuroimaging outcomes, and structural analyses of novel and recurrent variants of WDR62 gene in two consanguineous Pakistani families with autosomal recessive primary microcephaly

Article

Author: Rafiq, Shereen ; Asif, Maria ; Habib, Nida ; Asif, Roha ; Hussain, Muhammad Sajid ; Khan, Ramisha ; Makhdoom, Ehtisham Ul Haq ; Baig, Shahid Mahmood ; Saeed, Hafiza Iqra ; Akhtar, Roeha ; Anjum, Iram ; Bashir, Rasheeda ; Aslam, Komal ; Saeed, Aysha ; Abid, Hanna

BACKGROUNDAutosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD below mean) and often results in varying degree of intellectual disability. Thirty genes have been identified for the etiology of this disorder due to its clinical and genetic heterogeneity.METHODS AND RESULTSHere, we report two consanguineous Pakistani families affected with MCPH exhibiting mutation in WDR62 gene. The investigation approach involved Next Generation Sequencing (NGS) gene panel sequencing coupled with linkage analysis followed by validation of identified variants through automated Sanger sequencing and Barcode-Tagged (BT) sequencing. The molecular genetic analysis revealed one novel splice site variant (NM_001083961.2(WDR62):c.1372-1del) in Family A and one known exonic variant NM_001083961.2(WDR62):c.3936dup (p.Val1313Argfs*18) in Family B. Magnetic Resonance Imaging (MRI) scans were also employed to gain insights into the structural architecture of affected individuals. Neurological assessments showed the reduced gyral and sulcal patterns along with normal corpus callosum in affected individuals harboring novel variant. In silico assessments of the identified variants were conducted using different tools to confirm the pathogenicity of these variants. Through In silico analyses, both variants were identified as disease causing and protein modeling of exonic variant indicates subtle conformational alterations in prophesied protein structure.CONCLUSIONThis study identifies a novel variant (c.1372-1del) and a recurrent pathogenic variant c.3936dup (p.Val1313Argfs*18) in the WDR62 gene among the Pakistani population, expanding the mutation spectrum for MCPH. These findings emphasize the importance of genetic counseling and awareness to reduce consanguinity and address the burden of this disorder.

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Autosomal Recessive Primary Microcephaly

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