Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A case report

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The aetiology of Mayer\Rokitansky\K\üster\Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD\ =\ 33) c.705G\gt;T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.
OriginalsprogEngelsk
TidsskriftHuman Reproduction
ISSN0268-1161
DOI
StatusE-pub ahead of print - 1 aug. 2019

Citer dette

@article{473231bdcdb04456aa5bff9979faed5a,
title = "Whole-exome sequencing identifies a GREB1L variant in a three-generation family with M{\"u}llerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-K{\"u}ster-Hauser (MRKH) syndrome. A case report",
abstract = "The aetiology of Mayer\Rokitansky\K\{\"u}ster\Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD\ =\ 33) c.705G\gt;T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.",
author = "Herlin, {Morten K} and Le, {Vang Q} and T, {H Allan} and Anja Ernst and Henrik Okkels and Petersen, {Astrid C} and Petersen, {Michael B} and Pedersen, {Inge S}",
year = "2019",
month = "8",
day = "1",
doi = "10.1093/humrep/dez126",
language = "English",
journal = "Human Reproduction",
issn = "0268-1161",
publisher = "Oxford University Press",

}

TY - JOUR

T1 - Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A case report

AU - Herlin, Morten K

AU - Le, Vang Q

AU - T, H Allan

AU - Ernst, Anja

AU - Okkels, Henrik

AU - Petersen, Astrid C

AU - Petersen, Michael B

AU - Pedersen, Inge S

PY - 2019/8/1

Y1 - 2019/8/1

N2 - The aetiology of Mayer\Rokitansky\K\üster\Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD\ =\ 33) c.705G\gt;T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.

AB - The aetiology of Mayer\Rokitansky\K\üster\Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD\ =\ 33) c.705G\gt;T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.

U2 - 10.1093/humrep/dez126

DO - 10.1093/humrep/dez126

M3 - Journal article

JO - Human Reproduction

JF - Human Reproduction

SN - 0268-1161

ER -