Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Anazi, Shams; Maddirevula, Sateesh; Faqeih, Eissa; Alsedairy, Haifa; Alzahrani, Fatema; Shamseldin, Hanan E.; Patel, Nisha; Hashem, Mais; Ibrahim, Niema; Abdulwahab, Firdous; Ewida, Nour; Alsaif, Hessa S.; Sharif, Humayun; Alamoudi, W; Kentab, Amal Y.; Bashiri, Fahad A.; Alnaser, M; Alwadei, Ali H; Alfadhel, Majid; Eyaid, Wafaa; Hashem, Amal Al; Asmari, Ali Al; Saleh, Mohammed; Alsaman, Abdulaziz; Alhasan, Khalid; Al-Sughayir, Mohammed A.; Shammari, M Al; Mahmoud, Adel A.; Al‐Hassnan, Zuhair N.; Al-Husain, Muneera; Khalil, Rehab O.; Meguid, Nagwa A.; Masri, Amira; Ali, Rehab; Ben‐Omran, Tawfeg; El.Fishway, P; Hashish, Adel F.; Sencicek, A Ercan; State, Matthew W.; Alazami, Anas M.; Salih, Mustafa A.; Al-Tassan, Nada A.; Arold, Stefan T.; Abouelhoda, Mohamed; Wakil, Salma M.; Monies, Dorota; Shaheen, Ranad; Alkuraya, Fowzan S.

doi:10.1038/mp.2016.113

Cited by 208 publications

(210 citation statements)

References 46 publications

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“…We have previously shown that the mutation spectrum of genetically heterogeneous diseases is dominated by autosomal recessive mutations in our highly inbred populations (Patel et al 2015; Anazi et al 2016; Alazami et al 2016). We show in this study that cataract displays a similar trend with recessive mutations accounting for 87% of all identified mutations.…”

Section: Discussionmentioning

confidence: 94%

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

et al. 2016

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Pediatric cataract is highly heterogeneous clinically and etiologically. While mostly isolated, cataract can be part of many multisystem disorders, further complicating the diagnostic process. In this study, we applied genomic tools in the form of a multi-gene panel as well as whole-exome sequencing on unselected cohort of pediatric cataract (166 patients from 74 families). Mutations in previously reported cataract genes were identified in 58% for a total of 43 mutations, including 15 that are novel. GEMIN4 was independently mutated in families with a syndrome of cataract, global developmental delay with or without renal involvement. We also highlight a recognizable syndrome that resembles galactosemia (a fulminant infantile liver disease with cataract) caused by biallelic mutations in CYP51A1. A founder mutation in RIC1 (KIAA1432) was identified in patients with cataract, brain atrophy, microcephaly with or without cleft lip and palate. For nonsyndromic pediatric cataract, we map a novel locus in a multiplex consanguineous family on 4p15.32 where exome sequencing revealed a homozygous truncating mutation in TAPT1. We report two further candidates that are biallelically inactivated each in a single cataract family: TAF1A (cataract with global developmental delay) and WDR87 (non-syndromic cataract). In addition to positional mapping data, we use iSyTE developmental lens expression and gene-network analysis to corroborate the proposed link between the novel candidate genes and cataract. Our study expands the phenotypic, allelic and locus heterogeneity of pediatric cataract. The high diagnostic yield of clinical genomics supports the adoption of this approach in this patient group.

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Section: Discussionmentioning

confidence: 94%

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

et al. 2016

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“…There is no reported case of a deletion only in the FEZF2 gene with ID and/ or other phenotypic features that could support its importance in pathogenicity. However, the importance of FEZF2 for ID and developmental delay is shown in a recently described patient with a homozygous point mutation in the gene presenting with brain atrophy, suspected Dandy-Walker malformation, and microcephaly detected by cerebral MRI [Anazi et al, 2017]. Finally, the PTPRG tumor suppressor gene, which is outside of the suggested critical region [de la Hoz et al, 2015] and does 180 not seem to be relevant in the determination of ID and dysmorphisms (with a few exceptions) [Kranz et al, 2016], is also partially involved in our deletion.…”

Section: Discussionmentioning

confidence: 99%

A New 3p14.2 Microdeletion in a Patient with Intellectual Disability and Language Impairment: Case Report and Review of the Literature

Parmeggiani¹,

Buldrini²,

Fini³

et al. 2018

Mol Syndromol

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Interstitial deletions of chromosome 3p are rare, and specific genotype-phenotype correlations cannot always be assessed. We report the case of a 3p14.2 proximal microdeletion in a 60-year-old female patient with mild intellectual disability, severe speech delay, and mild dysmorphism. An array-CGH analysis detected a 500-kb deletion in the 3p14.2 region, including FEZF2, CADPS, and PTPRG. FEZF2 and CADPS are known to network within the neurodevelopmental pathways. It is possible that their rearrangements lead to the phenotypic features observed in the patient, and therefore, they can be considered candidate genes responsible for such abnormalities.

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“…These results indicate that Arg176 and Ala210 are critical for the glucose transport activity of SLC45A1. Anazi et al 10 recently reported a homozygous c.167T>C (p.Ile56Thr) missense mutation in SLC45A1 (or c.269T>C [p.Ile90Thr]; GenBank: NM_001080397.2) in a 5-year-old girl with developmental delay, ataxia, and Dandy-Walker malformation. Although this phenotype somewhat overlaps that of our affected individuals, none of our individuals had cerebellar abnormalities.…”

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confidence: 99%

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy

Srour

Shimokawa

Hamdan

et al. 2017

The American Journal of Human Genetics

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Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect wellconserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p ¼ 0.013) and 33% (p ¼ 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options.Glucose is the major energy fuel of the central nervous system. However, its availability is restricted given the selective permeability of the blood brain barrier (BBB) and the relative lack of carbohydrate stores in the brain. Thus, glucose transport across the BBB and into neural cells is critical for cerebral physiologic function and energy metabolism (for a review, see Chen et al. 1 ). GLUT1 is the key regulator of glucose across the BBB. 1 The importance of this process is illustrated by the observation that dominant mutations in SLC2A1 (OMIM: 138140), which encodes GLUT1, cause epilepsy with variable degrees of intellectual disability (ID) and/or movement disorder. 2 Once glucose enters the brain's extracellular space, it is taken up by different cerebral cells through various glucose transporters, which are expressed in developmentally and celltype-specific manners. Whether disruption of these neural glucose transporters also causes neurodevelopment disorders remains unknown.We report on four affected children from two unrelated consanguineous families with moderate to severe ID associated with epilepsy and variable neuropsychiatric features. Using whole-exome sequencing, we identified homozygous missense variants in SLC45A1 (OMIM: 605763), which codes for a neuronal glucose transporter that is predominantly expressed in the developing and adult brain. 3 Functional studies indicate that the identified variants reduce the activity of the protein, thus implicating SLC45A1 dysfunction in the etiology of ID a...

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Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Cited by 208 publications

References 46 publications

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

A New 3p14.2 Microdeletion in a Patient with Intellectual Disability and Language Impairment: Case Report and Review of the Literature

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy

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