High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases
Authors: Hiz Kurul Semra , Oktay Yavuz , Töpf Ana , Szabó Nóra Zs , Güngör Serdal , Yaramis Ahmet , Sonmezler Ece , Matalonga Leslie , Yis Uluc , Schon Katherine , Paramonov Ida , Kalafatcilar İpek Polat , Gao Fei , Rieger Aliz , Arslan Nur , Yilmaz Elmasnur , Ekinci Burcu , Edem Pinar Pulat , Aslan Mahmut , Özgör Bilge , Lochmüller Angela , Nair Ashwati , O'Heir Emily , Lovgren Alysia K ,   Broad Center for Mendelian Genomics, Maroofian Reza , Houlden Henry , Polavarapu Kiran , Roos Andreas , Müller Juliane S , Hathazi Denisa , Chinnery Patrick F , Laurie Steven , Beltran Sergi , Lochmüller Hanns , Horvath Rita 
Published: October 2021

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms.

We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations.

This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%).

We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.