Skip to main content

ADGRG1-related polymicrogyria syndrome: report on a large consanguineous family with a novel variant and review



Polymicrogyria is a spectrum of complex cortical malformations encompassing multiple subtypes. Of these, bilateral frontoparietal polymicrogyria (BFPP) has been associated with pathogenic variants in the ADGRG1 gene, formerly known as GPR56. BFPP is characterized by cognitive impairment, motor delay, seizures, oculomotor findings, cerebellar, pyramidal signs, and brain malformations that consist of abnormal changes in the cortex, white matter, brainstem, and cerebellum.

Case presentation

A large consanguineous Syrian family with five affected individuals exhibiting features of BFPP, is included in this study. These patients presented with cognitive impairment, psychomotor delay, epileptic episodes, cerebellar signs, oculomotor findings, and brain malformations. Through whole exome sequencing, a novel homozygous pathogenic variant in the ADGRG1 gene (NM_201525.4: c.308T > C; p.Leu103Pro) was identified.


Here, we report a thorough literature review of cases with BFPP, and we discuss the importance of genetic counseling in families with genetic disorders, especially in underdeveloped countries.


Polymicrogyria (PMG) is a heterogeneous disorder characterized by abundant small gyri and abnormal lamination of the cortex [1], representing nearly 20% of all cortical malformations [2]. Several forms of PMG are recognized based on their topographic patterns. These encompass perisylvian polymicrogyria, which represents the most prevalent pattern, along with generalized polymicrogyria, polymicrogyria accompanied by periventricular grey matter heterotopia, frontal polymicrogyria, parasagittal parieto-occipital polymicrogyria, among others [3]. Furthermore, these types are categorized into subtypes based on imaging findings [3].

Bilateral frontoparietal polymicrogyria (BFPP) is a symmetrical bilateral polymicrogyria with decreasing anterior to posterior gradient of severity, random white matter changes, cerebellar and brainstem hypoplasia, that are detected by MRI [4]. In 2004, variants in the ADGRG1 (Adhesion G protein coupled receptor G1) gene were linked to this disease [5]. ADGRG1 (MIM* 004110), located on chromosome 16q21, encodes an orphan G protein coupled receptor with a N-terminus, a proteolytic site, and seven transmembrane α helix C-terminal domains [6]. It is preferentially expressed in neuronal progenitor cells of the cerebral ventricles and subventricular zones during neurogenesis [5].

BFPP, inherited in an autosomal recessive manner [7, 8], is characterized by motor developmental delay, cognitive impairment, seizures, ataxia and dysconjugate gaze [9].

Here, we report a novel ADGRG1 pathogenic variant in a large consanguineous Syrian family, including five members affected with BFPP. A review of the literature is discussed and the importance of genetic counseling, especially in families with limited access to appropriate care, is highlighted.

Patients and methods


The patients are cousins from a multiply consanguineous Syrian family (Fig. 1). They presented to The Human Genetics Department in November 2022; and they have been thoroughly investigated by us for the past 10 months. Each of the family members underwent a work-up including a thorough clinical evaluation. and routine blood tests (complete blood count, serum electrolytes, blood glucose levels, cholesterol, thyroid, liver and renal function tests, and phosphatase alkaline levels). Extensive genetic testing was further done. Magnetic Resonance Imaging (MRI) was carried out following the institution’s standard clinical protocols, which typically involved acquiring axial, coronal, and sagittal Spin Echo T1 HF, Spin Echo T1, FSE T2, Fast FLAIR T2.

Fig. 1
figure 1

Pedigree of the family

Isolation of genomic DNA

Consent forms were collected from all family members. DNA was extracted from Leucocytes by standard salt-precipitation methods.

Whole exome sequencing

Whole exome sequencing (WES) was carried out on two affected individuals (V6 and V7) at 3billion Inc. Illumina NovaSeq 6000 system (San Diego, CA, USA) was used for sequencing as 150bp paired-end reads. Alignment to the GRCh37 human reference genome was done using BWA-MEM2, and samtools v1.15 was used for bam file sorting and marking duplicates [10, 11]. Recalibration and variant calling for single nucleotide variants (SNVs) and small insertion/deletion variants (indels) were performed using GATK v4.2 [12]. Structural variants (SVs) were called using CoNIFER 0.2.2v, and 3bCNV, an internally developed tool [13]. Variants were annotated, filtered, and classified using EVIDENCE v3.2 which incorporates Ensembl Variant Effect Predictor (VEP) for annotation and the American College of Medical Genetics and Genomics (ACMG) guideline for classification [14]. The filtered and classified variants were manually reviewed by medical geneticists and physicians. The most likely variants that can explain the patient’s phenotype were selected for reporting.

Sanger sequencing

The selected variant was studied in the patients V2 and V5 by Sanger sequencing. Genomic and cDNA sequences of ADGRG1 were obtained from UCSC Genomic Browser (NM_201525.4). Primers used for PCR amplification were designed using Primer3 software ( to amplify the region surrounding the mutation detected by exome sequencing. PCR products were purified by exonuclease I/Shrimp Alkaline Phosphatase treatment (ExoSAP-IT; Fisher Scientific SAS, Illkirch, France) according to the manufacturer’s instructions and both strands were sequenced using the Big Dye® Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems). Sequence reactions were purified on Sephadex G50 (Amersham Pharmacia Biotech, Foster City, CA) and capillary electrophoresis was performed on Genetic Analyser 3100 (Applied Biosystems). Electropherograms were analyzed on the Sequence Analysis Software version 5.2 (Applied Biosystems) and aligned with the wild-type SAMD9 gene sequence using ChromasPro version 1.22 (Technelysium, Queensland, Australia).

Clinical presentation

The family investigated in this study included 5 affected members (Fig. 1) born after normal vaginal deliveries without any exposure to pre- or perinatal environmental toxins. Psychomotor developmental delay was evident in all the patients in the first few months of life Indeed, limited social interaction, minimal verbal abilities without forming coherent words, inability to achieve toilet training and independent eating were observed in almost all cases. Individual V5 was the only sibling able to socially interact with his surroundings and to say a few words at the age of 4. Siblings V6 and V7 both suffered from oromotor dyspraxia. Patients V3, V5, V7 were not able to walk, and patients V2 and V6 started walking at 4 and 5 years of age, respectively. No dysmorphic features were noted in any of the patients. Microcephaly was noted in cases V6 and V7 (Table 1).

Table 1 Clinical features of the patients

Neurological examination revealed prominent ataxia, pyramidal signs, increased deep tendon reflexes and spasticity for V6 and V7; whereas, mild ataxia was only detected in patient V2. Moreover, individuals V5, V6 and V7 showed tone abnormalities. As for the oculomotor findings, strabismus was present in all individuals; and nystagmus was also detected in patients V6 and V7. Three patients (V5, V6 and V7) suffered from seizure episodes that were noted as early as the first couple of months for patients V6 and V7, or at age of 2 for patient V5. These were not resolved by medications and were still manifesting every 2 or 3 days in the mentioned cases (Table 1).

Imaging findings

A brain MRI performed for V2 at 1 year of age showed subcortical hyperintense signals with bilateral frontal–parietal and occipital topography, in addition to hyperintense zones in the periventricular and frontal horns areas. This was initially thought to be resulting from an infection with Herpes Simplex or Cytomegalovirus (CMV). Another brain MRI performed in this patient at age of 3 did not show any abnormality.

On the other hand, an MRI performed on the patient V5 at the age of 4 years showed the presence of a thick cortex of both cerebral hemispheres with sparse cortical sulci; multiple small hyperintense signal areas in the periventricular and deep white matter of both cerebral hemispheres. The lateral and third ventricles were mildly dilated, with normal fourth ventricles. The basal cisterns in both supra and infratentorial regions were prominent. These findings were first interpreted as being consistent with pachygyria–agyria complex (lissencephaly) (Fig. 2a).

Fig. 2
figure 2

a Axial T2 brain MRI of patient V5 displaying diffuse high signal intensity on T2 in the white matter alongside posterior polymicrogyria and pachygyria. b Axial FLAIR brain MRI of patient V6 revealing pachygyria and lissencephaly

MRI done on patient V6 at 1 year of age showed hyperintense signals in the periventricular and subcortical areas, accompanied by cerebral atrophy and secondary dilatation of the ventricular system. This was interpreted as lissencephaly (Fig. 2b).

The MRI of V7 performed at 4 years of age revealed an intraventricular cyst bulging into the lateral ventricles' posterior body. It was located inferior to the fornices which were displaced superiorly. There was no solid component, no calcifications, and the content followed CSF on all sequences. The occipital and temporal horns were prominent on the left, suggesting an impairment of the CSF flow caused by the cysts.

Genetic analysis

Whole exome sequencing was performed on patients V6 and V7. DNA was sequenced at 3billion using 3B-EXOME proband. A homozygous missense variation in the ADGRG1 gene (NM_201525.4: c.308T > C; p.Leu103Pro) was detected in both (Fig. 3). This variant was not observed in the gnomAD v2.1.1 dataset. Segregation analysis confirmed the presence of this variant in V6, and V7. In silico prediction tools suggest a damaging effect of the variant on the gene product (REVEL: 0.32; 3Cnet: 0.90).

Fig. 3
figure 3

Electropherogram showing the pathogenic variant identified at homozygous state in patient V6


Here, we describe five individuals with apparent brain malformations, intellectual disability, motor difficulties and seizures. Patients are descendants of a large Syrian family exhibiting many interrelated marriages. Whole exome sequencing carried out on two of the affected members, revealed a novel pathogenic variant in ADGRG; and sanger sequencing confirmed its segregation with the disease in the family; thus, supporting the diagnosis of BFPP.

To date, ADGRG1 pathogenic variants have been reported in a total of 92 patients [8, 15,16,17,18,19]. All reported cases show homogeneity in the following clinical features: intellectual disability, motor difficulties, epilepsy, cerebellar manifestations, and oculomotor abnormalities [20]. Table 2 illustrates the frequency of occurrence of the clinical characteristics related to BFPP, in the previously reported cases [8, 15,16,17,18,19]. The herein described cases mostly mirrored these findings. Similarly, to most of the reported cases (79.2%), cognitive impairment is severe to profound in the family herein studied. On clinical examination, ataxia, reflecting positive cerebellar signs, is noted in three of the five patients included. This finding is also observed in 88.9% of the previously reported cases with BFFP. As for the pyramidal signs which are noted in 75% of the reported cases, they were seen in two members of this family. Seizures were present in three of our patients (V5, V6, V7), which is consistent with the reported findings where 90.4% of the cases had seizures. On the other hand, unlike the present report where seizures were refractory to treatment in all the three patients, they are usually were refractory to medication in 54.7% of the reported cases. Furthermore, oculomotor findings were found in all the patients herein reported, entirely aligning with the previously reported cases. Likewise, as in several studies reporting abnormal tone [1, 15,16,17, 20,21,22], hypotonia was found in patients V5, V6 and V7; and hypertonia in V6 and V7. On the other hand, motor impairment is more severe in this family compared to reported patients with BFPP. In fact, while most of the BFPP cases mentioned in literature (70%) were able to walk at a median age of 3.5 years old [15], only two out of five of our patients (V2 and V6) managed to walk at 4 and 5 years, respectively. Besides, among our cases, three individuals exhibited strabismus, and two presented with both strabismus and nystagmus; the latter co-occurrence was only noted in 23.9% of cases. Oromotor dyspraxia, a rare feature of the disease [6, 23], was also observed in two of our patients. Last but not least, while dysmorphic features were noted in multiple cases in the literature [1, 5, 15, 21, 22, 24,25,26], our patients did not present any.

Table 2 Review of clinical features associated with BFPP syndrome

Interestingly, radiological findings in BFPP can mimic those observed in patients infected with Herpes Simplex or Cytomegalovirus (CMV); which may hinder the accurate diagnosis of patients presenting with this rare disease; as in patient V2 [17]. On the other hand, unlike all cases with BFPP showing radiological abnormalities, MRI performed during the first year of life of patient V3 was normal. Besides, radiological findings in patients V5 and V6 initially suggested lissencephaly [4, 27]. This further highlights the importance of genetic testing in readdressing the diagnosis of these patients, especially that radiological findings could be wrongly interpreted in underdeveloped countries with limited access to specialized centers. Genetic testing is also essential to enable the patients to benefit from an appropriate counseling, and help the family make informed choices in their future pregnancies, especially in underdeveloped areas that lack awareness about genetic diseases.


In conclusion, this is the first case report of BFPP in a consanguineous Syrian family. Our study reports a novel pathogenic variant in ADGRG1, and highlights the clinical heterogeneity of BFPP that manifests with variable intrafamilial expressivity.

Reporting patients with similar rare genetic disorders remains important to raise better awareness about these conditions and contribute to a better diagnosis and follow-up of patients affected with these diseases. This is much needed, especially in underdeveloped countries in our region which lack a well-founded databases such as the Catalogue for Transmission Genetics in Arabs (CTGA) Database [28].

Availability of data and materials

Not applicable.


  1. Chang BS, Piao X, Bodell A, Basel-Vanagaite L, Straussberg R, Dobyns WB et al (2003) Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 53(5):596–606

    Article  CAS  PubMed  Google Scholar 

  2. Polymicrogyria: a common and heterogeneous malformation of cortical development-Stutterd-2014-American Journal of Medical Genetics Part C: Seminars in Medical Genetics-Wiley Online Library [Internet]. [Cited 2023 May 25]. Available from:

  3. Leventer RJ, Jansen A, Pilz DT, Stoodley N, Marini C, Dubeau F et al (2010) Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. Brain 133(Pt 5):1415–1427

    Article  PubMed  PubMed Central  Google Scholar 

  4. Desai NA, Udani V (2015) GPR56-related polymicrogyria: clinicoradiologic profile of 4 patients. J Child Neurol 30(13):1819–1823

    Article  PubMed  Google Scholar 

  5. Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, Straussberg R et al (2004) G protein-coupled receptor-dependent development of human frontal cortex. Science 303(5666):2033–2036

    Article  CAS  PubMed  Google Scholar 

  6. Sawal HA, Harripaul R, Mikhailov A, Vleuten K, Naeem F, Nasr T et al (2018) Three mutations in the bilateral frontoparietal polymicrogyria gene GPR56 in Pakistani intellectual disability families. J Pediatr Genet 7(2):60–66

    Article  CAS  PubMed  Google Scholar 

  7. Singh AK, Lin HH (2021) The role of GPR56/ADGRG1 in health and disease. Biomed J 44(5):534–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kuo C, Tsai M, Lin H, Wang Y, Singh AK, Chang C et al (2023) Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral frontoparietal polymicrogyria: the electroclinical change from infancy to adulthood after callosotomy in three siblings. Epilepsia Open 8(1):154–164

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fujii Y, Ishikawa N, Kobayashi Y, Kobayashi M, Kato M (2014) Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria. Brain Dev 36(6):528–531

    Article  PubMed  Google Scholar 

  10. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N et al (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25(16):2078–2079

    Article  PubMed  PubMed Central  Google Scholar 

  11. Efficient Architecture-Aware Acceleration of BWA-MEM for Multicore Systems. In: IEEE Conference Publication, IEEE Xplore [Internet]. [Cited 2023 Nov 2]. Available from:

  12. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A et al (2010) The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Krumm N, Sudmant PH, Ko A, O’Roak BJ, Malig M, Coe BP et al (2012) Copy number variation detection and genotyping from exome sequence data. Genome Res 22(8):1525–1532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 17(5):405–423

    Article  PubMed  PubMed Central  Google Scholar 

  15. Carneiro F, Duarte J, Laranjeira F, Barbosa-Gouveia S, Couce ML, Fonseca MJ (2021) Case report: diffuse polymicrogyria associated with a novel ADGRG1 variant. Front Pediatr 27(9):728077

    Article  Google Scholar 

  16. Jha R, Kovilapu UB, Devgan A, Sondhi V (2022) Two novel compound heterozygous ADGRG1/GPR56 mutations associated with diffuse cerebral polymicrogyria. J Pediatr Genet 11(1):74–80

    Article  PubMed  Google Scholar 

  17. Bhanudeep S, Bhargavi B, Reddy S (2023) A clinico-radiologic mimicker of dystroglycanopathies and congenital cytomegalovirus infection. Neurol India 71(1):151

    Article  PubMed  Google Scholar 

  18. Khan S, Umair M, Abbas S, Ali U, Zaman G, Ansar M et al (2023) Overlapping neurological phenotypes in two extended consanguineous families with novel variants in the CNTNAP1 and ADGRG1 genes. J Gene Med 13:e3513

    Article  Google Scholar 

  19. Zulfiqar S, Tariq M, Ramzan S, Khan A, Sher M, Ali Z et al (2021) Identification of a novel variant in GPR56/ADGRG1 gene through whole exome sequencing in a consanguineous Pakistani family. J Clin Neurosci 94:8–12

    Article  CAS  PubMed  Google Scholar 

  20. Santos-Silva R, Passas A, Rocha C, Figueiredo R, Mendes-Ribeiro J, Fernandes S et al (2015) Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype. Neuropediatrics 46(2):134–138

    Article  CAS  PubMed  Google Scholar 

  21. Luo R, Yang HM, Jin Z, Halley DJJ, Chang BS, MacPherson L et al (2011) A novel GPR56 mutation causes bilateral frontoparietal polymicrogyria. Pediatr Neurol 45(1):49–53

    Article  PubMed  PubMed Central  Google Scholar 

  22. Borgatti R, Marelli S, Bernardini L, Novelli A, Cavallini A, Tonelli A et al (2009) Bilateral frontoparietal polymicrogyria (BFPP) syndrome secondary to a 16q12.1–q21 chromosome deletion involving GPR56 gene. Clin Genet 76(6):573–576

    Article  PubMed  Google Scholar 

  23. Quattrocchi CC, Zanni G, Napolitano A, Longo D, Cordelli DM, Barresi S et al (2013) Conventional magnetic resonance imaging and diffusion tensor imaging studies in children with novel GPR56 mutations: further delineation of a cobblestone-like phenotype. Neurogenetics 14(1):77–83

    Article  PubMed  Google Scholar 

  24. Piao X, Chang BS, Bodell A, Woods K, Benzeev B, Topcu M et al (2005) Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol 58(5):680–687

    Article  CAS  PubMed  Google Scholar 

  25. Dobyns WB, Patton MA, Stratton RF, Mastrobattista JM, Blanton SH, Northrup H (1996) Cobblestone lissencephaly with normal eyes and muscle. Neuropediatrics 27(2):70–75

    Article  CAS  PubMed  Google Scholar 

  26. Farah S, Sabry MA, Khuraibet A, Khaffagi S, Rudwan M, Hassan M et al (1997) Lissencephaly associated with cerebellar hypoplasia and myoclonic epilepsy in a Bedouin kindred: a new syndrome? Clin Genet 51(5):326–330

    Article  CAS  PubMed  Google Scholar 

  27. Cauley ES, Hamed A, Mohamed IN, Elseed M, Martinez S, Yahia A et al (2019) Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556. Neurogenetics 20(2):91–98

    Article  CAS  PubMed  Google Scholar 

  28. Bizzari S, Nair P, Deepthi A, Hana S, Al-Ali MT, Megarbané A et al (2021) catalogue for transmission genetics in arabs (CTGA) database: analysing lebanese data on genetic disorders. Genes (Basel) 12(10):1518

    Article  CAS  PubMed  Google Scholar 

Download references


We express our appreciation to the family for their cooperation throughout the study.


The authors received no financial support for the research authorship and / or publication of this article.

Author information

Authors and Affiliations



DEK, MH, SS, CM, EC, SWR, JK, AM have made a substantial contribution to the concept of the case report and the interpretation of data for the article; DEK, MH, SS, AM contributed to the follow-up and clinical evaluation of the patient. DEK, MH, CM and AM drafted the article content; All authors approved the version to be published;

Corresponding author

Correspondence to Andre Mégarbané.

Ethics declarations

Ethics approval and consent to participate

Approval to conduct the study was obtained from the Institutional Review Board of the Lebanese American University, Beirut, Lebanon. The IRB operates in compliance with the national regulations pertaining to research under the Lebanese Minister of Public Health’s Decision No.141 dated 27/1/2016 under LAU IRB Authorization reference 2016/3708, the international guidelines for Good Clinical Practice, the US Office of Human Research Protection (45CFR46) and the Food and Drug Administration (21CFR56). LAU IRB U.S. Identifier as an international institution: FWA00014723 and IRB Registration # IRB00006954 LAUIRB#1. Parents signed an informed consent for participation and sample collection.

Consent for publication

Parents signed an informed consent for data publication.

Competing interests

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El Khatib, D., Hojeij, M., Sabbagh, S. et al. ADGRG1-related polymicrogyria syndrome: report on a large consanguineous family with a novel variant and review. Egypt J Med Hum Genet 25, 54 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: