High diagnostic rate of trio exome sequencing in consanguineous families

Abstract

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.

C1 [Kurul, Semra Hiz; Oktay, Yavuz; Arslan, Nur] Dokuz Eylul Univ, Izmir Biomed & Genome Ctr, Hlth Campus, TR-35340 Izmir, Turkey.

[Kurul, Semra Hiz; Oktay, Yavuz; Sonmezler, Ece; Kalafatcilar, Ipek Polat; Yilmaz, Elmasnur; Ekinci, Burcu] Dokuz Eylul Univ, Izmir Int Biomed & Genome Inst, TR-35340 Izmir, Turkey.

[Kurul, Semra Hiz; Yis, Uluc; Kalafatcilar, Ipek Polat; Edem, Pinar Pulat] Dokuz Eylul Univ, Sch Med, Dept Paediat Neurol, TR-35340 Izmir, Turkey.

[Oktay, Yavuz] Dokuz Eylul Univ, Sch Med, Dept Med Biol, TR-35340 Izmir, Turkey.

[Topf, Ana] Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Inst Translat & Clin Res, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England.

[Szabo, Nora Zs] New St Johns Hosp, Epilepsy Neurol Polyclin, Buda Childrens Hosp, H-1023 Budapest, Hungary.

[Szabo, Nora Zs] Northern Buda United Hosp, H-1023 Budapest, Hungary.

[Gungor, Serdal; Aslan, Mahmut; Ozgor, Bilge] Inonu Univ, Fac Med, Turgut Ozal Res Ctr, Dept Paediat Neurol, TR-44210 Malatya, Turkey.

[Yaramis, Ahmet] Pediat Neurol Clin, TR-21070 Diyarbakir, Turkey.

[Matalonga, Leslie; Paramonov, Ida; Laurie, Steven; Beltran, Sergi; Lochmueller, Hanns] Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona 08003, Spain.

[Schon, Katherine; Gao, Fei; Muller, Juliane S.; Hathazi, Denisa; Chinnery, Patrick F.; Horvath, Rita] Univ Cambridge, Sch Clin Med, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge CB2 0XY, England.

[Schon, Katherine; Gao, Fei; Chinnery, Patrick F.] Univ Cambridge, MRC, Mitochondrial Biol Unit, Cambridge Biomed Campus, Cambridge CB2 0XY, England.

[Rieger, Aliz] Rehabil Ctr Phys Handicapped, H-1528 Budapest, Hungary.

[Arslan, Nur] Dokuz Eylul Univ, Sch Med, Dept Paediat Nutr & Metab, TR-1528 Izmir, Turkey.

[Lochmuller, Angela; Nair, Ashwati] Kings Coll London, GKT Sch Med Educ, London SE1 1UL, England.

[O'Heir, Emily; Lovgren, Alysia K.] Broad Inst MIT & Harvard, Program Med & Populat Genet, SE1 1UL, Cambridge, MA 02142 USA.

[Maroofian, Reza; Houlden, Henry] UCL, Natl Hosp Neurol & Neurosurg, Neurogenet Lab, London WC1N 3BG, England.

[Polavarapu, Kiran; Roos, Andreas; Lochmueller, Hanns] Univ Ottawa, Childrens Hosp Eastern Ontario Res Inst, 401 Smyth Rd,Res Bldg 2, Ottawa, ON K1H 8L1, Canada.

[Roos, Andreas] ISAS eV, Leibniz Inst Analyt Wissensch, D-44227 Dortmund, Germany.

[Roos, Andreas] Univ Duisburg Essen, Dept Pediat Neurol, D-45141 Essen, Germany.

[Muller, Juliane S.; Hathazi, Denisa; Horvath, Rita] Univ Cambridge, John Van Geest Ctr Brain Repair, Sch Clin Med, Dept Clin Neurosci, Cambridge CB2 0PY, England.

[Lochmueller, Hanns] Univ Freiburg, Fac Med, Dept Neuropediat & Muscle Disorders, Med Ctr, D-79106 Freiburg, Germany.

[Lochmueller, Hanns] Univ Ottawa, Ottawa Hosp, Div Neurol, Dept Med, Ottawa, ON, Canada.

[Lochmueller, Hanns] Univ Ottawa, Brain & Mind Res Inst, Ottawa, ON, Canada.