TY - JOUR
T1 - An update of pathogenic variants in ASPM, WDR62, CDK5RAP2, STIL, CENPJ, and CEP135 underlying autosomal recessive primary microcephaly in 32 consanguineous families from Pakistan
AU - Rasool, Sajida
AU - Baig, Jamshaid Mahmood
AU - Moawia, Abubakar
AU - Ahmad, Ilyas
AU - Iqbal, Maria
AU - Waseem, Syeda Seema
AU - Asif, Maria
AU - Abdullah, Uzma
AU - Makhdoom, Ehtisham Ul Haq
AU - Kaygusuz, Emrah
AU - Zakaria, Muhammad
AU - Ramzan, Shafaq
AU - Haque, Saif ul
AU - Mir, Asif
AU - Anjum, Iram
AU - Fiaz, Mehak
AU - Ali, Zafar
AU - Tariq, Muhammad
AU - Saba, Neelam
AU - Hussain, Wajid
AU - Budde, Birgit
AU - Irshad, Saba
AU - Noegel, Angelika Anna
AU - Höning, Stefan
AU - Baig, Shahid Mahmood
AU - Nürnberg, Peter
AU - Hussain, Muhammad Sajid
N1 - Publisher Copyright:
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Background: Primary microcephaly (MCPH) is a congenital neurodevelopmental disorder manifesting as small brain and intellectual disability. It underlies isolated reduction of the cerebral cortex that is reminiscent of early hominids which makes it suitable model disease to study the hominin-specific volumetric expansion of brain. Mutations in 25 genes have been reported to cause this disorder. Although majority of these genes were discovered in the Pakistani population, still a significant proportion of these families remains uninvestigated. Methods: We studied a cohort of 32 MCPH families from different regions of Pakistan. For disease gene identification, genome-wide linkage analysis, Sanger sequencing, gene panel, and whole-exome sequencing were performed. Results: By employing these techniques individually or in combination, we were able to discern relevant disease-causing DNA variants. Collectively, 15 novel mutations were observed in five different MCPH genes; ASPM (10), WDR62 (1), CDK5RAP2 (1), STIL (2), and CEP135 (1). In addition, 16 known mutations were also verified. We reviewed the literature and documented the published mutations in six MCPH genes. Intriguingly, our cohort also revealed a recurrent mutation, c.7782_7783delGA;p.(Lys2595Serfs*6), of ASPM reported worldwide. Drawing from this collective data, we propose two founder mutations, ASPM:c.9557C>G;p.(Ser3186*) and CENPJ:c.18delC;p.(Ser7Profs*2), in the Pakistani population. Conclusions: We discovered novel DNA variants, impairing the function of genes indispensable to build a proper functioning brain. Our study expands the mutational spectra of known MCPH genes and also provides supporting evidence to the pathogenicity of previously reported mutations. These novel DNA variants will be helpful for the clinicians and geneticists for establishing reliable diagnostic strategies for MCPH families.
AB - Background: Primary microcephaly (MCPH) is a congenital neurodevelopmental disorder manifesting as small brain and intellectual disability. It underlies isolated reduction of the cerebral cortex that is reminiscent of early hominids which makes it suitable model disease to study the hominin-specific volumetric expansion of brain. Mutations in 25 genes have been reported to cause this disorder. Although majority of these genes were discovered in the Pakistani population, still a significant proportion of these families remains uninvestigated. Methods: We studied a cohort of 32 MCPH families from different regions of Pakistan. For disease gene identification, genome-wide linkage analysis, Sanger sequencing, gene panel, and whole-exome sequencing were performed. Results: By employing these techniques individually or in combination, we were able to discern relevant disease-causing DNA variants. Collectively, 15 novel mutations were observed in five different MCPH genes; ASPM (10), WDR62 (1), CDK5RAP2 (1), STIL (2), and CEP135 (1). In addition, 16 known mutations were also verified. We reviewed the literature and documented the published mutations in six MCPH genes. Intriguingly, our cohort also revealed a recurrent mutation, c.7782_7783delGA;p.(Lys2595Serfs*6), of ASPM reported worldwide. Drawing from this collective data, we propose two founder mutations, ASPM:c.9557C>G;p.(Ser3186*) and CENPJ:c.18delC;p.(Ser7Profs*2), in the Pakistani population. Conclusions: We discovered novel DNA variants, impairing the function of genes indispensable to build a proper functioning brain. Our study expands the mutational spectra of known MCPH genes and also provides supporting evidence to the pathogenicity of previously reported mutations. These novel DNA variants will be helpful for the clinicians and geneticists for establishing reliable diagnostic strategies for MCPH families.
KW - ASPM
KW - CDK5RAP2
KW - CENPJ
KW - CEP135
KW - MCPH
KW - STIL
UR - http://www.scopus.com/inward/record.url?scp=85088143311&partnerID=8YFLogxK
U2 - 10.1002/mgg3.1408
DO - 10.1002/mgg3.1408
M3 - Article
C2 - 32677750
AN - SCOPUS:85088143311
SN - 2324-9269
VL - 8
JO - Molecular genetics & genomic medicine
JF - Molecular genetics & genomic medicine
IS - 9
M1 - e1408
ER -