ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
10556296 In 1999, Nanni et al. performed mutational analysis on SHH in 13 individuals with holoprosencephaly (HPE). The authors identified 4 deletions, 2 nonsense variants, and 1 insertion predicted to cause a truncated protein. 1 deletion in an individual with HPE caused a frameshift and was found in the individual?s sibling with developmental delay and their mother with a single central incisor and loss of smell. Another deletion was a sporadic, de novo case. Yet another deletion was identified in a healthy mother of a deceased fetus with HPE who was not tested for SHH variants. 1 nonsense variant was confirmed de novo. Another was identified in a fetus with HPE and their sibling with a phenotype including a single central incisor and microcephaly while their parents were not carriers. Lastly, the insertion variant was found in an individual with HPE and their 2 siblings with HPE had the variant as well.
12567406 In 2003, Marini et al. studied a family with autosomal dominant holoprosencephaly (HPE) by using PCR and direct sequencing to identify variants in SHH. Affected family members consisted of a mother with single central maxillary incisor, her daughter with alobar HPE, a miscarried fetus with HPE, and a fetus with alobar HPE from a terminated pregnancy. In each of these individuals, the nonsense variant c.383G>A was identified.
22791840 In 2015, Solomon et al. analyzed the genotype-phenotype relationship between 396 individuals with holoprosencephaly (HPE) from 157 different families. 98 of these families had more than 1 family member affected. Of the individuals in the study, some were patients identified by the National Institutes of Health (NIH), while others were identified from previously published studies. The authors noted that the NIH patients underwent sequencing according to methodology elaborated upon in Roessler et. al 2009 (PMID: 19603532), which involved a combination of PCR, denaturing high-pressure liquid chromatography (dHPLC) analysis, and direct DNA sequencing. Solomon et. al identified 141 different SHH variants. Of these variants, 21 were nonsense, 17 were frameshifts, 7 were in-frame deletions and insertions, and 2 were splice site variants. 83 of the 157 probands had what the author described as ?frank? HPE as opposed to a microform or simply no HPE. Per the authors, ?individuals with frank HPE were universally severely cognitively impaired, and microcephaly and hypotelorism were very commonly reported in those with available data? The authors then compared cases of frank HPE caused by truncating variants to the cases caused by missense variants. 63 truncating variants caused frank HPE while 65 did not. Additionally, non-truncating variants resulted in 73 frank HPE cases and 138 non-HPE cases. The difference between the outcomes caused by these variants was found to be significant, with truncating variants more frequently resulting in frank HPE. Of note, the authors reflected that non-HPE (microforms or no HPE) cases were significantly overrepresented in SHH cases as opposed to cases involving other HPE genes like SIX3 and ZIC2.

Haploinsufficiency phenotype comments:

A number of heterozygous sequence-level variants have been described in patients with holoprosencephaly (HPE) spectrum conditions. While all currently reported SHH deletions include nearby genes, functional data suggest focal SHH deletion would also increase the risk for HPE and related phenotypes. See GeneReviews for discussion of variable phenotypic expression. Additional cases: PMID: 8896572 In 1996, Roessler et al. studied 30 families with autosomal dominant holoprosencephaly (ADHPE) to identify causative variants in SHH. Their methods for identifying variants involved the use of single-strand confirmation polymorphism (SSCP) analysis on all 30 families, followed by DNA sequencing of 2 individuals from each family found to have SSCP band shifts. Analysis revealed that 5 families had variants in SHH; 2 of these families had variants which introduced a stop codon and was predicted to be truncating. In 1 of these families, the variant was present in an affected mother and her 2 sons. In the other family, 9 affected individuals had the nonsense variant and were affected, while one individual had the variant and was not affected. The specific phenotypes of each individual with a truncating variant and described as affected by ADHPE was not explicitly noted. PMID: 29321670 In 2018, Asadollahi et al. used whole exome sequencing (WES) on 13 Swiss patients with acrocallosal syndrome (ACLS) to identify causative variants. In a 29-year-old patient, a de novo frameshift variant was identified in SHH. Per the authors, the individual had, ?facial features of broad and high forehead, hypertelorism, flat nasal root, thin upper and everted lower lips, and retracted but relatively large chin.? PMID: 29498412 In 2018, Bruel et al. used whole exome sequencing (WES) on a 10-year-old presenting with iris coloboma, hypotelorism, developmental delay, and microcephaly. WES was also used on their family members. Analysis identified a nonsense variant in SHH in the 10-year-old. Additionally, this variant was identified in the proband?s sister, brother, mother, and grandmother. The brother, sister, and mother had learning difficulties and microcephaly. The mother also had coloboma. The grandmother was microcephalic. Of note, the proband?s uncle had died as an infant and per the authors had, ?microcephaly, coloboma, hypotelorism, median cleft lip, and encephalopathy.?

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
19431187 2009 report of a maternally inherited duplication encompassing SHH in a patient with semilobar HPE. The functional consequence of this duplication is unknown. No coordinates are provided for the duplication, and it is unclear if it is intragenic, if it involves other genes, etc.