Ahmad I, Baig S M, Abdulkareem A R, Hussain M S, Sur I, Toliat M R, Nürnberg G, Dalibor N, Moawia A, Waseem S S, Asif M, Nagra H, Sher M, Khan M M A, Hassan I, Rehman S Ur, Thiele H, Altmüller J, Noegel A A, Nürnberg P
Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
Clin Genet. 2017 Jul;92(1):62-68. doi: 10.1111/cge.12955. Epub 2017 Feb 22.
Autosomal recessive primary microcephaly (MCPH) is a rare and heterogeneous genetic disorder characterized by reduced head circumference, low cognitive prowess and, in general, architecturally normal brains. As many as 14 different loci have already been mapped. We recruited 35 MCPH families in Pakistan and could identify the genetic cause of the disease in 31 of them. Using homozygosity mapping complemented with whole-exome, gene panel or Sanger sequencing, we identified 12 novel mutations in 3 known MCPH-associated genes - 9 in ASPM, 2 in MCPH1 and 1 in CDK5RAP2. The 2 MCPH1 mutations were homozygous microdeletions of 164,250 and 577,594 bp, respectively, for which we were able to map the exact breakpoints. We also identified four known mutations - three in ASPM and one in WDR62. The latter was initially deemed to be a missense mutation but we demonstrate here that it affects splicing. As to ASPM, as many as 17 out of 27 MCPH5 families that we ascertained in our sample were found to carry the previously reported founder mutation p.Trp1326*. This study adds to the mutational spectra of four known MCPH-associated genes and updates our knowledge about the genetic heterogeneity of MCPH in the Pakistani population considering its ethnic diversity.
常染色体隐性原发性小头畸形（MCPH）是一种罕见的、具有遗传异质性的疾病，其特征为头围减小、认知能力低下，总体而言大脑结构正常。目前已定位了多达14个不同的基因座。我们在巴基斯坦招募了35个MCPH家庭，其中31个家庭的疾病遗传病因得以明确。通过纯合性定位，并辅以全外显子组、基因panel或桑格测序，我们在3个已知的与MCPH相关的基因中鉴定出12个新突变——9个在ASPM基因中，2个在MCPH1基因中，1个在CDK5RAP2基因中。这2个MCPH1突变分别为164,250和577,594 bp的纯合微缺失，我们能够确定其确切的断点。我们还鉴定出4个已知突变——3个在ASPM基因中，1个在WDR62基因中。后者最初被认为是错义突变，但我们在此证明它影响剪接。至于ASPM基因，在我们样本中确定的27个MCPH家庭中，多达17个被发现携带先前报道的始祖突变p.Trp1326*。这项研究丰富了4个已知的与MCPH相关基因的突变谱，并考虑到巴基斯坦人群的种族多样性，更新了我们对MCPH遗传异质性的认识。
