Clinical characteristics: Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Diagnosis/testing: Before the molecular basis was known, the diagnosis of CSS was based on clinical findings. With the recent detection of heterozygous pathogenic variants in <i>ARID1A</i>, <i>ARID1B</i>, <i>SMARCA4</i>, <i>SMARCB1</i>, <i>SMARCE1</i>, or <i>SOX11</i> in some (but not all) individuals with CSS, the diagnostic features have become more clearly described for classic cases. A few individuals diagnosed with CSS on a clinical basis have been found to have pathogenic variants in <i>SMARCA2</i> or <i>PHF6</i>; on reevaluation, the phenotype of these individuals was most consistent with Nicolaides-Baraitser syndrome or Borjeson-Forssman-Lehmann syndrome, respectively.
Management: <i>Treatment of manifestations:</i> Occupational, physical, and/or speech therapies to optimize developmental outcomes. Feeding therapy, nutritional supplementation and/or gastrostomy tube placement as needed to meet nutritional needs. Routine management of ophthalmologic abnormalities and hearing loss. <i>Surveillance:</i> Yearly evaluation by a developmental pediatrician to assess developmental progress and therapeutic and educational interventions; follow up with a gastroenterologist and feeding specialists as needed to monitor feeding and weight gain. Routine follow up of ophthalmologic and/or audiologic abnormalities.
Genetic counseling: CSS caused by a heterozygous pathogenic variant in one of six genes (<i>ARID1A</i>, <i>ARID1B, SMARCA4, SMARCB1, SMARCE1,</i> and <i>SOX11</i>) is inherited in an autosomal dominant manner, but most commonly results from a <i>de novo</i> pathogenic variant. If the pathogenic variant has been identified in a family member, prenatal testing for pregnancies at increased risk is possible.
GeneReviews<sup>®</sup> 1993;University of Washington, Seattle
The ARID1B phenotype: what we have learned so far.
Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.
American journal of medical genetics. Part C, Seminars in medical genetics 2014;166C;3;276-89