Clinical, neuroimaging, and molecular spectrum of
            <i>TECPR2</i>
            ‐associated hereditary sensory and autonomic neuropathy with intellectual disability

Neuser, Sonja; Brechmann, Barbara; Heimer, Gali; Brösse, Ines; Schubert, Susanna; O’Grady, Lauren; Zech, Michael; Srivastava, Siddharth; Sweetser, David A.; Dincer, Yasemin; Mall, Volker; Winkelmann, Juliane; Behrends, Christian; Darras, Basil T.; Graham, Robert J.; Jayakar, Parul; Byrne, Barry J.; Bar-Aluma, Bat El; Haberman, Yael; Szeinberg, Amir; Aldhalaan, Hesham; Hashem, Mais; Tenaiji, Amal Al; Ismayl, Omar; Nuaimi, Asma E Al; Maher, Karima; Ibrahim, Shahnaz; Khan, Fatima; Houlden, Henry; Ramakumaran, Vijayalakshmi Salem; Pagnamenta, Alistair T.; Posey, Jennifer E.; Lupski, James R.; Tan, Wen‐Hann; ElGhazali, Gehad; Herman, Isabella; Muñoz, T. De Haro; Repetto, Gabriela M.; Seitz, Angelika; Krumbiegel, Mandy; Poli, Cecilia; Kini, Usha; Efthymiou, Stéphanie; Meiler, Jens; Maroofian, Reza; Alkuraya, Fowzan S.; Jamra, Rami Abou; Popp, Bernt; Ben‐Zeev, Bruria; Ebrahimi‐Fakhari, Darius

doi:10.1002/humu.24206

Cited by 24 publications

(31 citation statements)

References 38 publications

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“…The likelihood of disease due to mutation in MTHFR thus diminishes the candidacy of alternative RASAL2, MAGEB2 and PCDHA9/10. Similarly, for trio IAH2, a biallelic LoF in TECPR2 -a gene which has been reported for autosomal recessive spastic paraplegia 49 (SPG49; MIM 615031) as well as for autosomal recessive ID (Anazi et al, 2017) and hereditary sensory neuropathy with ID (Neuser et al, 2021) -also lessens the case for the PCDHA9/10 biallelic loss CNV. For trio IABB2, the biallelic LoF mutation in DEAF1 -a gene associated with an AR neurodevelopmental disorder with hypotonia, impaired expressive language, with or without seizures (NEDHELS; MIM 617171) -seems a highly probable candidate, and thus diminishes the possible involvement of biallelic loss CNVs at UBE2U and SHPK.…”

Section: Discussionmentioning

confidence: 80%

Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

Harripaul

Rabia

Vasli

et al. 2021

Preprint

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Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that affects about 1 in 55 children worldwide and imposes enormous economic and socioemotional burden on families and communities. Genetic studies of ASD have identified de novo copy number variants (CNVs) and point mutations that contribute significantly to the genetic architecture of ASD, but the majority of these studies were conducted in outbred populations, which are not ideal for detecting autosomal recessive (AR) inheritance. However, several studies have investigated ASD genetics in consanguineous populations and point towards AR as an under-appreciated source of ASD variants. Here, we used trio whole exome sequencing (WES) to look for rare variants for ASD in 115 proband-mother-father trios from populations with high rates of consanguinity, namely Pakistan, Iran, and Saudi Arabia. In total, we report 87 candidate sequence variants, with 57% biallelic, 21% autosomal dominant/de novo, and the rest X-linked. 52% of the variants were loss of function (LoF) or putative LoF (splice site, stop loss) and 47% non-synonymous. Our analysis indicates an enrichment of previously identified and candidate AR genes. These include variants in genes previously reported for AR ASD and/or intellectual disability (ID), such as AGA, ASL, ASPA, BTN3A2, CC2D1A, DEAF1, HTRA2, KIF16B, LINS1, MADD, MED25, MTHFR, RSRC1, TECPR2, VPS13B, ZNF335, and 32 previously unreported candidates, including 15 LoF or splice variants, in genes such as DAGLA, EFCAB8, ENPP6, FAXDC2, ILDR2, PKD1L1, SCN10A, and SLC36A1. We also identified candidate biallelic exonic loss CNVs a number of trios, implicating genes including DNAH7, and DHRS4/DHRS4L2.

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Section: Discussionmentioning

confidence: 80%

Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

Harripaul

Rabia

Vasli

et al. 2021

Preprint

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“…Protein tertiary structures were visualized using Pymol (v2.5.0, Schroedinger, LLC, New York, NY, USA). CADD PHRED scores (v1.6) of all possible base substitutions of the CAPN1 transcript were computed and mapped to the corresponding protein sequence 7 . All variants were harmonized to NM_001198868.2/GRCh38/hg38.…”

Section: Methodsmentioning

confidence: 99%

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

Alecu

Saffari

Jumo

et al. 2022

Ann Clin Transl Neurol

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CAPN1‐associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain‐1 function. Here we illustrate a translational approach to the case of an 18‐year‐old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound‐heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop‐gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain‐1 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.

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“…In family 1, we performed RT-PCR as described previously [ 19 ] using PAXgene RNA in the parents and fetal skeletal muscle RNA derived cDNA. In family 3, we performed RNA-seq from PAXgene RNA using the TruSeq RNA Library Prep Kit v2 and paired-end sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…Disease-associated missense analysis in the linear protein, clustering analysis in 3D and structural modeling of missense variants using the crystal structure 2BRF [ 22 ] was performed as described previously [ 11 , 13 , 19 ] and is detailed in the Supplementary notes .…”

Section: Methodsmentioning

confidence: 99%

Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain

Neuser

Krey

Schwan³

et al. 2021

Eur J Hum Genet

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Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot–Marie–Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C intrans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.

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Clinical, neuroimaging, and molecular spectrum of TECPR2 ‐associated hereditary sensory and autonomic neuropathy with intellectual disability

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 24 publications

References 38 publications

Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

Autism spectrum disorder trios from consanguineous populations are enriched for rare biallelic variants, identifying 32 new candidate genes

Novel CAPN1 missense variants in complex hereditary spastic paraplegia with early‐onset psychosis

Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain

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