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=11 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

This study aims to clinically and genetically assess 30 unrelated consanguineous Pakistani families from various ethnic backgrounds, all exhibiting features of neurodevelopmental disorders (NDDs).

Methods

We conducted clinical, genetic, biochemical, and molecular analyses on 30 consanguineous families with NDDs enrolled from various regions of Pakistan. The likely molecular causes of primary microcephaly and NDDs were identified. Detailed clinical investigations and molecular diagnoses were performed using whole exome sequencing (WES) of the proband, followed by Sanger sequencing for validation and segregation in the available family members of the affected families.

Results

WES identified likely disease-causing homozygous variants in 30 unrelated consanguineous families. Six families presented newly described variants in known NDD-related genes: ABAT (c.1439 T > G; p.Phe480Cys) [OMIM613163], SLC12A6 (c.2865_2865insT; p.Glu955Asnfs*5) [OMIM 218000], SHANK3 (c.1305-3_1,305-2delTT; 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]. Additionally, 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 autosomal recessive inheritance.

Conclusion

In the present study, we observed a high frequency of ASPM variants in the genetic analysis of 30 consanguineous families exhibiting features of NDDs, particularly those associated with autosomal recessive primary microcephaly. These findings contribute to studies on genotype–phenotype correlation, genetic counseling for families, and a deeper understanding of human brain function and development.