A large, ten‐generation family with autosomal dominant preaxial polydactyly/triphalangeal thumb: Historical, clinical, genealogical, and molecular studies

Abstract

We present a large, ten-generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid-1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiological studies of most of the affected members have been performed for 42 years (follow-up of the family by LFGA). Molecular studies have confirmed a pathogenic variant in the ZRS that segregates in this family. To the best of our knowledge, this is the largest family with preaxial polydactyly/triphalangeal thumb reported so far.

ORIGINAL ARTICLEA large, ten-generation family with autosomal dominantpreaxial polydactyly/triphalangeal thumb: Historical, clinical,genealogical, and molecular studiesLuis Francisco González ́Alvarez1| Jair Tenorio-Castaño2,3,4|Fernando A. Poletta5,6,7| Fernando Santos-Simarro2,3,4| Pedro Arias2,3|Natalia Gallego2,3,4| Iêda Maria Orioli5,6,7| Stefan Mundlos8,9|Eduardo E. Castilla5,6,7| Víctor Martínez-Glez2,3,4| María Luisa Martínez-Frías10|Víctor L. Ruiz-Pérez2,4,11| Julián Nevado2,3,4| Pablo Lapunzina2,3,41Centro de Salud Area 6, Madrid, Spain2CIBERER, Centro de Investigacion Biomédica en Red de Enfermedades Raras, Madrid, Spain3INGEMM-Idipaz, Institute of Medical and Molecular Genetics, Madrid, Spain4ITHACA, European Reference Network, Brussels, Belgium5ECLAMC at CEMIC (Center for Medical Education and Clinical Research) and CONICET (National Council for Scientific and Technical Investigation), Buenos Aires,Argentina6ECLAMC (Latin American Collaborative Study of Congenital Malformations) at INAGEMP (National Institute of Population Medical Genetics), Rio de Janeiro, Brazil7Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil8Institute of Medical and Human Genetics, Charité Universitätsmedizin, Berlin, Germany9Max Planck Institute for Molecular Genetics, Berlin, Germany10ECEMC, Estudio Colaborativo Español de Malformaciones Congénitas and CIAC, ISCIII, Madrid, Spain11Instituto de Investigaciones Biomédicas Alberto Sols, IIB-UAM, Madrid, SpainCorrespondencePablo Lapunzina, INGEMM-Instituto deGenética Médica y Molecular, Madrid, Spain;IdiPAZ-Instituto de Investigacion Sanitaria delHospital Universitario La Paz-UniversidadAutonoma de Madrid, Madrid, Spain;CIBERER-Centro de Investigacion Biomédicaen Red de Enfermedades Raras, Madrid, Spain;ISCIII, Madrid- Paseo de la Castellana261-28046, Madrid, Spain.Email:pablo.lapunzina@salud.madrid.org;plapunzina@ciberer.esJair Tenorio-Castaño, INGEMM-Instituto deGenética Médica y Molecular, Madrid, Spain;IdiPAZ-Instituto de Investigacion Sanitaria delHospital Universitario La Paz-UniversidadAutonoma de Madrid, Madrid, Spain;CIBERER-Centro de Investigacion Biomédicaen Red de Enfermedades Raras, Madrid, Spain;ISCIII, Madrid- Paseo de la Castellana261-28046, Madrid, Spain.Email:jairantonio.tenorio@salud.madrid.orgAbstractWe present a large, ten-generation family of 273 individuals with 84 people havingpreaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone ofpolarizing activity regulatory sequence (ZRS) within the exon 5 ofLMBR1. The causa-tive change maps to position 396 of the ZRS, located at position c.423+4909C > T(chr7:156791480; hg38;LMBR1ENST00000353442.10; rs606231153NG_009240.2) in the intron 5 ofLMBR1. The first affected individual with the disor-der was traced back to mid-1700, when some settlers and workers established inCer-vera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiologicalstudies of most of the affected members have been performed for 42 years (follow-up of the family by LFGA). Molecular studies have confirmed a pathogenic variant inthe ZRS that segregates in this family. To the best of our knowledge, this is the larg-est family with preaxial polydactyly/triphalangeal thumb reported so far.Luis Francisco González ́Alvarez and Jair Tenorio-Castaño contributed equally to this work.Received: 9 March 2022 Revised: 5 July 2022 Accepted: 19 August 2022DOI: 10.1002/ajmg.a.62994Am J Med Genet.2022;1–8.wileyonlinelibrary.com/journal/ajmga© 2022 Wiley Periodicals LLC.1

Funding informationInstituto de Salud Carlos III, Grant/AwardNumber: PI20/01053KEYWORDSintron 5 ofLMBR1, polarizing activity regulatory sequence, preaxial polydactyly, semidominantinheritance, triphalangeal thumb, ZRS1|INTRODUCTIONPreaxial polydactyly is a relatively uncommon and complex congenitalanomaly with a general prevalence of 2.08/10,000 births (Castillaet al.,1973; Orioli & Castilla,1999). Preaxial polydactyly is an error inthe anteroposterior axis of the limbs development. Currently, this con-genital anomaly is viewed as a spectrum of severity of multiple embry-onic events (Al-Qattan,2018; Al-Qattan et al.,2012).Preaxial polydactyly II, triphalangeal thumb-polysyndactyly syn-drome (TPTPS) and isolated triphalangeal thumb type I (all three, MIM#174500) and hypoplasia of the tibia with polydactyly (also known asWerner mesomelic syndrome; WMS; MIM #188770) can all be causedby pathogenic variants in the sonic hedgehog (SHH) regulatory ele-ment denominated ZRS (zone of polarizing activity regulatorysequence). The ZRS is a long-range limb-specificSHHenhancer. Inhumans, the ZRS is located on chromosome 7q36 within the intron5 of theLMBR1gene approximately 1 Mb telomeric toSHH.Multiple genetic and genomic alterations have been observedwithin the ZRS region (Figure6). In addition to preaxial polydactyly/triphalangeal thumb, single nucleotide variants (SNVs) and duplica-tions of the ZRS lead to variable phenotypes such as tibial aplasia/hypoplasia with radial ray deficiency (MIM #188740) and type IVfamilial syndactyly (syndactyly of all digits with polydactyly or Haastype polysyndactyly; MIM #186200). The ZRS is conserved amongmammals and fish and regulates the expression ofSHH. In mice, theconserved ZRS within theLmbr1gene is located in chromosome5. The Hammertoe (Hm) mutant mouse has a pathogenic variant attheLmbr1locus and shows a phenotypic manifestation of syndactylyof digits 2–5 without polydactyly (Al-Qattan,2018; Al-Qattanet al.,2012).Several families and isolated case reports of preaxial polydactyly/triphalangeal thumb have been published in the literature (Potuijtet al.,2019); most of them with genetic confirmation studies support-ing the molecular cause of this complex disorder.In this article, we describe an exceptionally large, ten-generationfamily of 273 individuals with 84 people affected with preaxial poly-dactyly/triphalangeal thumb. The first individual of this family affectedwith the disorder was traced back to mid-1700, when some settlersand workers established inCervera de Buitrago(geolocation:+40,921,1013,531,020; 405501400North 33105000West), a smallhilly village 82 km North to Madrid (Figure4). Clinical and radiologicalstudies of most of them have been performed over the last 40 years.Our molecular studies have confirmed a pathogenic variant within theZRS region that segregates with the disease in this family (Figure3).Currently, four affected individuals at child-bearing age have beenincluded in a pre-implantation genetic diagnosis program to avoid thetransmission of the disease. To our best knowledge, this would be thelargest family with preaxial polydactyly/triphalangeal thumb reportedso far.2|PATIENTS AND METHODSWe identified a large family with 273 people and 84 affected patients(Figure1). All patients have either preaxial polydactyly of hands ofvariable degree of severity and/or triphalangeal thumbs. Only a minor-ity (four individuals) presented polydactyly of both feet with or with-out two to three toe cutaneous syndactyly.Clinical evaluation was conducted for 53 affected and 65 non-affected individuals. Radiological studies were performed in most ofthem (Figure2).We extracted DNA from 19 affected individuals (identified asindividuals # 117, 118, 125, 134, 144, 160, 162, 163, 166, 179,195, 198, 204, 206, 209, 211, 214, 222, 224, in the pedigree) and2 non-affected. Initially, we performed an analysis of genomic rearran-gements in three of them by applying an oligo genome-wide microar-ray (Karyorray™) as reported in (Vallespin et al.,2013) with a non-conclusive result. We then looked for specific variants in the ZRSregion by PCR amplification of this region (primer sequences availableupon request). Amplicons were subsequently analyzed by Sangersequencing.3|RESULTSAll affected patients analyzed with preaxial polydactyly/triphalangealthumb presented a pathogenic change in the ZRS region. In non-affected family members who were sequenced, the variant was notfound. The change maps to position 396 of the ZRS region, at positionc.423+4909C > T of the ZRS region (chr7:156791480; hg38;LMBR1ENST00000353442.10; rs606231153 NG_009240.2) in the intron5ofLMBR1.Most patients presented the C396T variant in the heterozygousstate except individuals 117 and 209 who had this variant in homozy-gosis (Figures2and3). Homozygous patients inherited the C396Tvariant from both parents and were clinically indistinguishable fromthose with the variant in heterozygous state. In line with thegenotype–phenotype segregation pattern, PCR analysis of individuals144 and 221 without neither preaxial polydactyly/triphalangeal thumbnor polydactyly, did not present the pathogenic variants in the ZRSregion (Figures1and3).X-rays showed a variable degree of compromise of the first raysand triphalangeal thumbs in most of them. Heptadactyly, with twoadditional preaxial digits, was observed in only 13 individuals.2 ́ALVAREZET AL.

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A large, ten-generation family with autosomal dominant preaxial polydactyly/triphalangeal thumb: Historical, clinical, genealogical, and molecular studies

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A large, ten-generation family with autosomal dominant preaxial polydactyly/triphalangeal thumb: Historical, clinical, genealogical, and molecular studies

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