Introduction
As the use of carrier screening and number of conditions screened expands, the scope of disorders that can be diagnosed prenatally widens. Subsequently, the number of conditions in newborn screening has also increased. Multiple studies such as The NBSeq Project, The BabySeq Project, and Early Check have explored the utility of introducing sequencing into newborn screening, newborn exome sequencing, or even genome sequencing (GS). However, the plethora of information large-scale sequencing yields has also posed considerations for incidental findings, variants of uncertain significance, and conditions with incomplete penetrance or variable expressivity. These questions become more nuanced in the setting of prenatal or product of conception (POC) sequencing (recurrence risk, availability and accessibility of pre-implantation genetic testing) as demonstrated by the following case of Sheldon-Hall syndrome, an incompletely penetrant and variably expressive condition, diagnosed on POC through GS.

Case Presentation
A 32-year-old G2P0010 with unremarkable personal and family history presented for routine consultation to discuss prenatal screening and testing options. She elected prenatal cell-free DNA screening (cfDNA) and expanded carrier screening for 112 conditions (X-linked and autosomal recessive); both resulted as low risk. She later presented at 23w3d gestational age after her anatomy ultrasound revealed bilateral underdevelopment of the three middle digits of the hands and mild micrognathia.

Diagnostic Workup
The patient elected termination at 23w5d; POC testing yielded normal chromosome analysis and chromosome microarray results. GS was performed through the FirstSEQ study at Columbia, revealing a paternally inherited, heterozygous pathogenic variant in TNNT3 (c.188G>A). Monoallelic pathogenic variants in this gene are associated with Arthrogryposis, distal, type 2B2, also known as Sheldon-Hall syndrome.

Treatment and Management
The patient and her partner were counseled on Sheldon-Hall syndrome, which presents with variable distal skeletal anomalies including arthrogryposis, overlapping fingers, ulnar deviation of fingers and/or wrists, clinodactyly, vertical talus, varus deformity, club foot, and sandal gap. Short middle fingers and micrognathia have been observed in individuals. These congenital anomalies are not thought to be progressive. Characteristic facies include a webbed neck and short stature. Intelligence and lifespan are generally not affected. There is enough inter- and intrafamilial variability in phenotypic expression for the mildest cases to be consistent with reduced penetrance. The specific variant detected in this case has been previously noted in a large family with some individuals harboring this variant having subtle clinical phenotypes. The consultand’s partner denied known personal or family history of associated features. Autosomal dominant inheritance, incomplete penetrance, and variable expressivity was reviewed, and reproductive options including in vitro fertilization (IVF) with preimplantation genetic testing (PGT) were discussed.

Outcome and Follow-Up
The consultand and her partner expressed feelings of conflict between aversion towards experiencing another similarly affected pregnancy, concerns about costs involved in IVF and PGT, and motivation for PGT for an incompletely penetrant, variably expressive condition in context of lack of known family history.

Discussion
‘Arthrogryposis’ is a term which describes the feature of congenital, multiple contracted joints, shared among over 400 reported conditions. Most cases of arthrogryposis are thought to be sporadic. Through GS, a rare hereditary etiology of arthrogryposis was identified that has yet to impact the individual health of obligate and/or presumed carriers in this family. Further exploration of guidelines and ongoing discussions to help patients answer these questions should be encouraged to optimize utility and equitable access to follow-up care following such diagnoses.

Conclusion
GS can be useful tool for assessing molecular etiologies of seemingly sporadic malformations, but also poses clinical and bioethical questions in preconception and prenatal genetic counseling.