AUTHOR=Paracha Sohail Aziz , Nawaz Shoaib , Tahir Sarwar Muhammad , Shaheen Asmat , Zaman Gohar , Ahmed Jawad , Shah Fahim , Khwaja Sundus , Jan Abid , Khan Nida , Kamal Mohammad Azhar , Alam Qamre , Abbas Safdar , Farman Saman , Waqas Ahmed , Alkathiri Afnan , Hamadi Abdullah , Santoni Federico , Ullah Naseeb , Khalid Bisma , Antonarakis Stylianos E. , Fakhro Khalid A , Umair Muhammad , Ansar Muhammad 

TITLE=The genetic cause of neurodevelopmental disorders in 30 consanguineous families

JOURNAL=Frontiers in Medicine

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1424753

DOI=10.3389/fmed.2024.1424753

ISSN=2296-858X

ABSTRACT=Objective
Clinically and genetically assessment of 30 unrelated consanguineous Pakistani families with various ethnic backgrounds exhibiting features of neurodevelopmental disorders.
Methods
We performed clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with neurodevelopmental disorders enrolled from various areas of Pakistan in which the likely molecular cause of the primary microcephaly and NDD has been identified. Detailed clinical investigation and molecular diagnosis were performed using Whole Exome Sequencing (WES) of the proband, followed by Sanger sequencing for the available members of affected families for validation and segregation. 
Results
WES revealed likely disease-causing homozygous variants in 30 consanguineous unrelated families. Six families had newly described variants in known NDD-related genes; [ABAT (c.1439T>G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865_2865insT; p.Glu955Asnfs*5) [OMIM 218000],  SHANK3 (c.1305-3_1305-2delTT; p.Gln29-_Gly305del) [OMIM 606232], BCKDK (c.356_356insC; p.Gly119Alafs*24) [OMIM 614923],  DDHD2 (c.2065G>T; p.Asp689Tyr) [OMIM 615033],  ERCC2 (c.1255G>A; p.Glu419Lys) [OMIM 610756] and 12 families had previously  reported disease-causing variants associated with different types of  NDDs; [ATRX (c.109C>T; p.Arg37*)[OMIM 309580], GPR56 [ADGRG1] (c.1423C>T; p.Arg475*)[OMIM 606854], NAGLU (c.1694G>A; p.Arg565Gln) [OMIM 252920],  DOLK (c.3G>A; p.Met1Ile) [OMIM 610768], GPT2 (c.815C>T; p.Ser272Leu) [OMIM 616281],  DYNC1I2 (c.607+1G>A; p.?) [OMIM 618492], FBXL3 (c.885delT; p.Leu295Phefs25*)[OMIM 606220],  LINGO1 (c.869G>A; p.Arg290His) [OMIM 618103] and ASPM (c.3978G>A; Trp1326*, c.9557C>G; p.Ser3186*, c.6994C>T; p.Arg2332*) [OMIM 608716]. All the identified variants showed segregation compatible with an autosomal recessive inheritance.
Conclusions
We observed a high frequency of ASPM variants after genetic analysis of 30 consanguineous families exhibiting features of neurodevelopmental disorders in the present study associated with autosomal recessive primary microcephaly and associated NDDs. These findings contribute to studies of genotype-phenotype correlation, genetic counseling of the families, and further understanding of human brain function and development.