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Genetics of Primary Microcephaly and Intellectual Disability
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Genetics of Primary Microcephaly and Intellectual Disability

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 July 2021) | Viewed by 17199

Special Issue Editor

Dr. Muhammad Sajid Hussain

E-Mail Website
Guest Editor
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
Interests: neurodevelopmental disorders; intellectual disability; primary microcephaly; epilepsy; functional genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Human brain size increased dramatically due to a disproportionate increase in the volume of the cerebral cortex which is thought to underlie increased intellectual capacity to execute complex cognitive functions. It is the product of millions of years of multifaceted evolution, operating intricately towards its structural and functional optimization, which stays an enigma to modern science. Primary microcephaly (PM) and intellectual disability (ID) are the manifestations of the disruption in these processes and studying their etiologies unravel the indispensable components of normal brain functions—every new study adds a new piece to the puzzle.

Besides enticing scientific curiosity, PM and ID has serious socioeconomical implications as well. Worldwide prevalence is estimated to range from 1% to 3% (ID) and 1/10,000–1/100,000 (PM), which is higher in developing as compared to developed countries. Due to substantial limitations in both intellectual functionings and adaptive behavior, these disorders severely compromises the quality of life of not only the patients, but also casts a serious burden on their afflicted families, and the social and health care system. Multiple factors such as malnutrition, cultural deprivation, poor health care provision have been traditionally attributed to explain non-inherited etiology.

Technological limitations were confining the studies to the genetic causes of familial and sporadic cases. But the latest and robust genomic technologies now available have opened the avenues to explore their genetic causes. These hold the potential to identify the most crucial, thus inherently most vulnerable components of normal brain function. Therefore, this Special Issue focuses on the identification of genetic events causing PM and ID and their underlying pathomechanisms.
      

Kind regards,  

Dr. Muhammad Sajid Hussain
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neurodevelopmental disorders
  • Brain development
  • Intellectual disability
  • Primary microcephaly
  • De novo mutations
  • Inherited familial mutations
  • Linkage analysis
  • Exome sequencing
  • Functional genomics
  • Transcriptome profiling

Published Papers (5 papers)

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14 pages, 1079 KiB  
Article
Rare Pathogenic Variants in Genes Implicated in Glutamatergic Neurotransmission Pathway Segregate with Schizophrenia in Pakistani Families
by Ambrin Fatima, Uzma Abdullah, Muhammad Farooq, Yuan Mang, Mana M. Mehrjouy, Maria Asif, Zafar Ali, Niels Tommerup and Shahid M. Baig
Genes 2021, 12(12), 1899; https://doi.org/10.3390/genes12121899 - 26 Nov 2021
Cited by 2 | Viewed by 2261
Abstract
Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare [...] Read more.
Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders. Full article
(This article belongs to the Special Issue Genetics of Primary Microcephaly and Intellectual Disability)
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13 pages, 2305 KiB  
Article
A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family
by Syeda Seema Waseem, Abubakar Moawia, Birgit Budde, Muhammad Tariq, Ayaz Khan, Zafar Ali, Sheraz Khan, Maria Iqbal, Naveed Altaf Malik, Saif ul Haque, Janine Altmüller, Holger Thiele, Muhammad Sajid Hussain, Sebahattin Cirak, Shahid Mahmood Baig and Peter Nürnberg
Genes 2021, 12(10), 1494; https://doi.org/10.3390/genes12101494 - 24 Sep 2021
Cited by 3 | Viewed by 2940
Abstract
Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as [...] Read more.
Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA’s localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and common to rapidly degraded proteins. An impaired function of the PEST domains may affect the intracellular half-life of the protein. Our genetic findings compellingly substantiate the predicted candidacy, based on its newly ascribed functional features, of the multifaceted protein AKNA for association with MCPH. Full article
(This article belongs to the Special Issue Genetics of Primary Microcephaly and Intellectual Disability)
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16 pages, 1731 KiB  
Article
Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism
by Natalie Young, Maria Asif, Matthew Jackson, Daniel Martín Fernández-Mayoralas, Mar Jimenez de la Peña, Beatriz Calleja-Pérez, Sara Álvarez, Eve Hunter-Featherstone, Angelika A. Noegel, Wolfgang Höhne, Peter Nürnberg, Boguslaw Obara, Muhammad Sajid Hussain, Iakowos Karakesisoglou and Alberto Fernández-Jaén
Genes 2021, 12(9), 1294; https://doi.org/10.3390/genes12091294 - 24 Aug 2021
Cited by 5 | Viewed by 4733
Abstract
Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting [...] Read more.
Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD. Full article
(This article belongs to the Special Issue Genetics of Primary Microcephaly and Intellectual Disability)
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18 pages, 1654 KiB  
Article
Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ
by Ehtisham Ul Haq Makhdoom, Syeda Seema Waseem, Maria Iqbal, Uzma Abdullah, Ghulam Hussain, Maria Asif, Birgit Budde, Wolfgang Höhne, Sigrid Tinschert, Saadia Maryam Saadi, Hammad Yousaf, Zafar Ali, Ambrin Fatima, Emrah Kaygusuz, Ayaz Khan, Muhammad Jameel, Sheraz Khan, Muhammad Tariq, Iram Anjum, Janine Altmüller, Holger Thiele, Stefan Höning, Shahid Mahmood Baig, Peter Nürnberg and Muhammad Sajid Hussainadd Show full author list remove Hide full author list
Genes 2021, 12(5), 731; https://doi.org/10.3390/genes12050731 - 13 May 2021
Cited by 7 | Viewed by 3794
Abstract
Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this [...] Read more.
Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment. Full article
(This article belongs to the Special Issue Genetics of Primary Microcephaly and Intellectual Disability)
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8 pages, 7331 KiB  
Case Report
De Novo 1q21.3q22 Duplication Revaluation in a “Cold” Complex Neuropsychiatric Case with Syndromic Intellectual Disability
by Roberta Milone, Roberta Scalise, Rosa Pasquariello, Stefano Berloffa, Ivana Ricca and Roberta Battini
Genes 2021, 12(4), 511; https://doi.org/10.3390/genes12040511 - 31 Mar 2021
Viewed by 2235
Abstract
Syndromic intellectual disability often obtains a genetic diagnosis due to the combination of first and next generation sequencing techniques, although their interpretation may require revaluation over the years. Here we report on a composite neuropsychiatric case whose phenotype includes moderate intellectual disability, spastic [...] Read more.
Syndromic intellectual disability often obtains a genetic diagnosis due to the combination of first and next generation sequencing techniques, although their interpretation may require revaluation over the years. Here we report on a composite neuropsychiatric case whose phenotype includes moderate intellectual disability, spastic paraparesis, movement disorder, and bipolar disorder, harboring a 1.802 Mb de novo 1q21.3q22 duplication. The role of this duplication has been reconsidered in the light of negativity of many other genetic exams, and of the possible pathogenic role of many genes included in this duplication, potentially configuring a contiguous gene-duplication syndrome. Full article
(This article belongs to the Special Issue Genetics of Primary Microcephaly and Intellectual Disability)
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