Molecular Characteristics

The multiple congenital anomaly syndrome is caused by biallelic sequence variations in the HHAT (Hedgehog acyltransferase) gene. HHAT encodes an acetyltransferase that is involved in post-translational modifications, particularly the process of palmitoylation (lipid modification) of the core hedgehog proteins. These core hedgehog proteins include IHH (Indian hedgehog), DHH (Desert hedgehog) and SHH (Sonic hedgehog). These downstream proteins involved in the pathway are implicated in a wide range of functioning including limb patterning, maintenance of antero-posterior and left-right symmetry, development of limbs, somites, nervous system, eyes, bones, cartilage and muscles.
The sequence variants in IHH are associated with acrocapitofemoral dysplasia (OMIM# 607778) and brachydactyly, type A1 (OMIM# 112500). The sequence variants in DHH are known to cause 46XY sex reversal 7 (OMIM# 233420). While single nucleotide variants, indels or copy number variants in SHH are associated with holoprosencephaly 3 (OMIM# 142945), microphthalmia with coloboma 5 (OMIM# 611638), schizencephaly (OMIM# 269160), single median maxillary central incisor (OMIM# 147250). HHAT-related multiple congenital anomalies syndrome appears to have combination of clinical features of the conditions resulting from aberrant functioning of these three genes.

Till date, seven affected individuals from three unrelated families are reported. Out of the seven reported individuals, molecular testing was performed for three affected individuals (from three unrelated families) and their unaffected parents.

The three reported biallelic sequence variants (transcript ID: NM_001122834.3) till date are

1. A nonsynonymous variant, c.860G>T; p.(Gly287Val) in exon 8 of HHAT
2. A nonsynonymous variant, c.770T>C; p.(Leu257Pro) in exon 7 of HHAT
3. An in frame deletion, c.365_367del; p.(Thr122del) in exon 5 of HHAT

The variants reported in HHAT are likely to cause complete loss of function of HHAT leading to the defective downstream signaling by disrupting the ability of HHAT to palmitoylate hedgehog proteins leading to further phenotypic consequences as seen in all the affected families.

With the extreme phenotypic variability, the best testing method available as of today for diagnosing this clinical entity is exome sequencing.