Coffin-Siris syndrome

Recommended panel testing at Breda Genetics for this condition:

Coffin-Siris syndrome (ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCE1, SOX11)

The fifth digit syndrome

Asian baby finger

Coffin-Siris syndrome (also known as fifth digit syndrome) is a very rare genetic syndrome. Even though the condition is highly variable, the main hallmarks are abnormalities of the fifth finger, developmental disability of variable grade, hirsutism and coarse facial features.

Clinical features

The abnormality of the fifth digit consists in the absence or hypoplasia of the distal phalanx of the fifth digit or toe. Clinodactyly of the fifth finger and hypoplasia of the distal phalanx of the II, III and IV toes have also been reported in some cases.

Intellectual disability ranges from mild to severe and can be associated with delayed development of speech and motor skills (walking and sitting). Patients usually show low weight at birth, generalized hypotonia, and microcephaly. Coarse facial features are mainly consistent with wide nose with anteverted nostrils and flat nasal bridge, wide mouth with thick lips, thick eyebrows, synophrys. Hirsutism (excessive hair) can be seen on the face and other parts of the body.

Recurrent respiratory infections and airway obstruction due to choanal atresia are frequent.

Variable clinical stigmata include: cardiac anomalies, Dandy-Walker malformation, choanal atresia, small patellas, inguinal and umbilical hernia, rectal prolapse, suction and feeding difficulties, reduced fetal activity, intrauterine growth retardation (IUGR), hyperphosphatemia, hydronephrosis, hypoglycemia, and premature thelarche with early development of the mammal glands.


Coffin Siris is a very rare condition with an unconfirmed preponderance in females (although such bias might be due to underdiagnosed hirsutism in males). All reported cases have occurred sporadically. In some patients heterozygous pathogenic mutations have been detected in the ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1SMARCE1, and SOX11 genes. Mutations in these genes are associated with autosomal dominant transmission, although most mutations appear to be de novo (i.e. not inherited from the parents). Autosomal recessive inheritance might occur in some families where the syndrome recurred in siblings who tested negative in the aforementioned genes (although recurrence in siblings might also be explained by parental germline mosaicism for dominant mutations). An individual with mosaic trisomy 9 had features resembling Coffin-Siris syndrome, including facial features (wide, bulbous nose), hirsutism, and hypoplasia of the fifth digits. Overall, a molecular confirmation of the syndrome is still missing in about 10% of patients with an evocative clinical phenotype.


No formal clinical criteria have been thus far determined to establish the diagnosis, so that molecular genetic testing is of primary importance to confirm the syndrome. Targeted sequencing and deletion/duplication testing of the known genes may detect pathogenic mutations in a majority of patients. Whole exome sequencing may reveal pathogenic mutations in known and as-yet-unknown genes while enabling immediate differential diagnosis with similar conditions such as Nicolaides-Baraitser and Cornelia de Lange syndromes.

Differential Diagnosis

The differential diagnosis of Coffin-Siris syndrome includes the following clinical entities:

  • Nicolaides-Baraitser syndrome and Cornelia de Lange syndrome (CdLS)
  • Brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome (OMIM 113477)
  • Deafness, onychodystrophy, osteodystrophy, and “mental retardation” (DOOR) syndrome
  • Fetal alcohol spectrum
  • Fetal anticonvulsant syndrome (also known as fetal hydantoin/phenytoin embryopathy)
  • Mabry syndrome/ hyperphosphatasia with mental retardation syndrome 1 (OMIM 239300)
  • 4q deletion syndrome

Recommended testing workflow

Due to genetic heterogeneity and the possibility of as yet unknown associated genes, Coffin-Siris syndrome is a perfect candidate to panel testing based on clinical exome sequencing or whole exome sequencing. Our recommended panel testing for this condition are the following:

Coffin-Siris syndrome (ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCE1, SOX11)


Histone-modification disorders and their differential diagnosis (incl. Wiedemann-Steiner, Kabuki, Coffin-Siris, Nicolaides-Baraitser, and Cornelia de Lange syndromes) (ARID1A, ARID1B, ARID2, DPF2, HDAC8, NIPBL, KMT2A, KMT2D, KDM6A, SMARCA2, SMARCA4, SMARCB1, SMARCE1, SMC1A, SMC3, SOX11, RAD21)


Mental retardation with absent fifth fingernail and terminal phalanx. Coffin GS, Siris E. Am J Dis Child. 1970 May;119(5):433-9. PMID: 5442442

Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N. Nat Genet. 2012 Mar 18;44(4):376-8. PMID: 22426308

Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y, Wessels MW, den Hollander NS, Ruivenkamp CA, van Ommen GJ, Breuning MH, den Dunnen JT, van Haeringen A, Kriek M. Nat Genet. 2012 Mar 18;44(4):379-80. PMID: 22426309

Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing. Kosho T, Miyake N, Carey JC. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):241-51. PMID: 25169878

Coffin-Siris Syndrome. Schrier Vergano S, Santen G, Wieczorek D, Wollnik B, Matsumoto N, Deardorff MA. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2013 Apr 4 [updated 2018 Feb 8]. PMID: 23556151

Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype. Bramswig NC, Caluseriu O, Lüdecke HJ, Bolduc FV, Noel NC, Wieland T, Surowy HM, Christen HJ, Engels H, Strom TM, Wieczorek D. Hum Genet. 2017 Mar;136(3):297-305. PMID: 28124119

Mutations in the BAF-Complex Subunit DPF2 Are Associated with Coffin-Siris Syndrome. Vasileiou G, Vergarajauregui S, Endele S, Popp B, Büttner C, Ekici AB, Gerard M, Bramswig NC, Albrecht B, Clayton-Smith J, Morton J, Tomkins S, Low K, Weber A, Wenzel M, Altmüller J, Li Y, Wollnik B, Hoganson G, Plona MR, Cho MT; Deciphering Developmental Disorders Study, Thiel CT, Lüdecke HJ, Strom TM, Calpena E, Wilkie AOM, Wieczorek D, Engel FB, Reis A. Am J Hum Genet. 2018 Mar 1;102(3):468-479. PMID: 29429572

Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome. Hempel A, Pagnamenta AT, Blyth M, Mansour S, McConnell V, Kou I, Ikegawa S, Tsurusaki Y, Matsumoto N, Lo-Castro A, Plessis G, Albrecht B, Battaglia A, Taylor JC, Howard MF, Keays D, Sohal AS; DDD Collaboration, Kühl SJ, Kini U, McNeill A. J Med Genet. 2016 Mar;53(3):152-62. PMID: 26543203

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