Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability

Thuresson, Ann‐Charlotte; Zander, Cecilia; Zhao, Jinyan; Halvardson, Jonatan; Maqbool, Khurram; Månsson, Else; Stenninger, Eric; Holmlund, Ulrika; Öhrner, Ylva; Feuk, Lars

doi:10.1111/cge.13470

Cited by 16 publications

(13 citation statements)

References 5 publications

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“…We report on the fifth case of Steel syndrome outside of the Puerto Rican population, here caused by compound heterozygosity of two novel predicted null mutations in COL27A1 . Our patient's clinical presentation matches the clinical features of Steel syndrome described in previous patients, including typical facial dysmorphy, short stature, kyphoscoliosis, malalignment of multiple large joints including congenital bilateral hip dislocation, and hearing impairment (Figure and Table ; Flynn et al, ; Gariballa et al, ; Kotabagi et al, ; Maddirevula et al, ; Thuresson et al, ).…”

Section: Discussionsupporting

confidence: 86%

“…The homozygous missense mutation identified in the original family was also found in other affected individuals of Puerto Rican ancestry and constitutes a founder effect in that population (Belbin et al, ; Gonzaga‐Jauregui et al, ). Four additional reports of patients from outside Puerto Rico with other COL27A1 mutations have extended the phenotypic spectrum of Steel syndrome by including hearing loss and—possibly—developmental delay (Gariballa et al, ; Kotabagi, Shah, Shukla, & Girisha, ; Maddirevula et al, ; Thuresson et al, ). Here, we describe a patient with Steel syndrome and bilateral colobomata of the eyes who is compound heterozygous for two novel COL27A1 putative null mutations c.93del and c.3075del.…”

Section: Introductionmentioning

confidence: 99%

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A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye

Pölsler

Schatz

Simma

et al. 2020

American J of Med Genetics Pt A

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The joint occurrence of short stature, congenital dislocation of the hip, carpal coalition, dislocation of the radial head, cavus deformity, scoliosis, and vertebral anomalies was first described in 1993 by Steel et al. (OMIM #615155) in 23 children from Puerto Rico. The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi‐allelic loss of function mutations in the gene COL27A1. Outside of Puerto Rico, only four families have been described, in three of which the patients also had hearing loss. However, structural eye defects have not yet been reported in conjunction with this rare autosomal recessive syndrome. Here, we describe a 9‐year‐old girl born to nonconsanguineous Syrian parents with the characteristic features of Steel syndrome, including short stature, massive malalignment of large joints, kyphoscoliosis, hearing loss, and typical facial dysmorphism. However, she was also born with bilateral colobomata of the irides and choroido‐retinae with unilateral affection of the macula. Whole exome sequencing identified two pathogenic compound heterozygous variants in COL27A1: c.93del, p.(Phe32Leufs*71) and c.3075del, p.(Lys1026Argfs*33). There was no discernible alternative cause for the colobomata. Our findings might indicate an association of this exceptionally rare disorder caused by COL27A1 mutations with developmental defects of the eye from the anophthalmia/microphthalmia/coloboma spectrum.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye

Pölsler

Schatz

Simma

et al. 2020

American J of Med Genetics Pt A

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“…They reached a consensus that surgery to repair dislocations is not advisable because it leads to a poor outcome with recurrent hip dislocations (Flynn et al, 2010;Gonzaga-Jauregui et al, 2015;Steel et al, 1993). The causative gene, COL27A1, was not identified until 2015 by Gonzaga-Jauregui et al Only 11 patients have previously been published with COL27A1 mutations (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015;Kotabagi, Shah, Shukla, & Girisha, 2016;Maddirevula et al, 2019;Thuresson et al, 2019). Eight of these patients had an apparent founder mutation, p.Gly697Arg in the Puerto Rican population (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015).…”

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confidence: 99%

“…Eight of these patients had an apparent founder mutation, p.Gly697Arg in the Puerto Rican population (Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015). Three patients were described with other mutations in COL27A1 and were not from Puerto Rico (Kotabagi et al, 2016;Maddirevula et al, 2019;Thuresson et al 2019). The 37 patients described prior to 2015 (Flynn et al, 2010;Steel et al, 1993) have not had genetic testing described in the literature.…”

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confidence: 99%

“…Dr. Flynn was able to re-examine 18 of the 23 children originally seen in 1993. However, the Flynn et al (2010) paper does not distinguish which patients were previously evaluated, so it is unclear which patients did or did not receive follow up in 2010.Additionally, 11 more patients have been reported(Belbin et al, 2017;Gariballa et al, 2016;Gonzaga-Jauregui et al, 2015;Kotabagi et al, 2016;Maddirevula et al, 2019;Thuresson et al, 2019). In total, 48 patients have been previously published with the diagnosis of Steel Syndrome.…”

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confidence: 99%

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Three new patients with Steel syndrome and a Puerto Rican specific COL27A1 mutation

Amlie‐Wolf

Moyer-Harasink

Carr

et al. 2020

American J of Med Genetics Pt A

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Steel syndrome was initially described by H. H. Steel in 1993 in Puerto Rico, at which time he described the clinical findings required for diagnosis. The responsible gene, COL27A1, was identified in 2015 (Gonzaga‐Jauregui et al., European Journal of Human Genetics, 2015;23:342–346). Eleven patients have previously been described with Steel syndrome and homozygous COL27A1 mutations, with eight having an apparent founder mutation, p.Gly697Arg. We describe three more patients identified at Einstein Medical Center Philadelphia and St. Christopher's Hospital for Children (Philadelphia, PA) diagnosed with Steel syndrome. All three are of Puerto Rican ancestry with the previously described founder mutation and had either hip dislocations or hip dysplasia. Radial head dislocation was only identified in one patient while short stature and scoliosis were noted in two of these patients. There are now 51 patients in the literature with Steel syndrome, including the 3 patients in this article, and 14 patients with a genetically confirmed Steel syndrome diagnosis.

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A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability

Li,

Kang,

Zou

et al. 2023

Neurogenetics

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Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability

Cited by 16 publications

References 5 publications

A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye

A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye

Three new patients with Steel syndrome and a Puerto Rican specific COL27A1 mutation

A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability

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